JPH0582395B2 - - Google Patents
Info
- Publication number
- JPH0582395B2 JPH0582395B2 JP59262700A JP26270084A JPH0582395B2 JP H0582395 B2 JPH0582395 B2 JP H0582395B2 JP 59262700 A JP59262700 A JP 59262700A JP 26270084 A JP26270084 A JP 26270084A JP H0582395 B2 JPH0582395 B2 JP H0582395B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- kanamycin
- fluoro
- deoxykanamycin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- -1 alkali metal hydrogen Chemical class 0.000 claims description 29
- 229960001192 bekanamycin Drugs 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000006239 protecting group Chemical group 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 16
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 15
- 229910052783 alkali metal Inorganic materials 0.000 claims description 15
- 229930182824 kanamycin B Natural products 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- 125000001160 methoxycarbonyl group Chemical class [H]C([H])([H])OC(*)=O 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 9
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical class C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- 125000003754 ethoxycarbonyl group Chemical class C(=O)(OCC)* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- BFXAWOHHDUIALU-UHFFFAOYSA-M sodium;hydron;difluoride Chemical group F.[F-].[Na+] BFXAWOHHDUIALU-UHFFFAOYSA-M 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 claims description 4
- 150000001340 alkali metals Chemical group 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 claims description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- SKKLOUVUUNMCJE-FQSMHNGLSA-N kanamycin B Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SKKLOUVUUNMCJE-FQSMHNGLSA-N 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- 229960000318 kanamycin Drugs 0.000 description 6
- 229930182823 kanamycin A Natural products 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- ASZZHBXPMOVHCU-UHFFFAOYSA-N 3,9-diazaspiro[5.5]undecane-2,4-dione Chemical compound C1C(=O)NC(=O)CC11CCNCC1 ASZZHBXPMOVHCU-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229920005654 Sephadex Polymers 0.000 description 4
- 239000012507 Sephadex⢠Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 229940126574 aminoglycoside antibiotic Drugs 0.000 description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 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
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 229930027917 kanamycin Natural products 0.000 description 3
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229930182825 Kanamycin C Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910001515 alkali metal fluoride Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 2
- WZDRWYJKESFZMB-FQSMHNGLSA-N kanamycin C Chemical compound O([C@H]1[C@H](N)C[C@@H]([C@H]([C@@H]1O)O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)N)N)[C@H]1O[C@H](CO)[C@@H](O)[C@H](N)[C@H]1O WZDRWYJKESFZMB-FQSMHNGLSA-N 0.000 description 2
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CFOGIGZVKWLSHG-UHFFFAOYSA-N 2-(aminomethyl)-6-[4,6-diamino-3-(4-amino-3,5-dihydroxy-6-methyloxan-2-yl)oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol Chemical class OC1C(N)C(O)C(C)OC1OC1C(O)C(OC2C(C(O)C(O)C(CN)O2)O)C(N)CC1N CFOGIGZVKWLSHG-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001513 alkali metal bromide Inorganic materials 0.000 description 1
- 229910001514 alkali metal chloride Inorganic materials 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 125000006627 ethoxycarbonylamino group Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000006626 methoxycarbonylamino group Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000006248 tosyl amino group Chemical group [H]N(*)S(=O)(=O)C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
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The present invention describes a novel semi-synthetic aminoglycoside antibiotic, 3'-fluoro-3'-deoxykanamycin B.
and its manufacturing method. This new compound exhibits high antibacterial activity against various kanamycin-susceptible and kanamycin-resistant bacteria and is useful as an antibacterial agent. Various deoxy derivatives of kanamycin A, B, and C are known as semisynthetic aminoglycoside antibiotics derived from kanamycin A, B, and C. Although these previously known deoxykanamycin derivatives have useful antibacterial activity, their antibacterial spectrum varies widely and new resistant bacteria may emerge and render them ineffective, so new and better antibacterial agents are needed. There is a constant desire to create chemical compounds. The present inventor has discovered that kanamycin A
If we can create a derivative in which the hydroxyl group at the 3' position is replaced with a fluoro group, that is, 3'-fluoro-3'-deoxykanamycin A, we expect that this will be a compound that is effective against kanamycin-resistant bacteria. succeeded in synthesizing. That is, the present inventors disclosed in the previous Japanese Patent Application No. 161615/1989 (see Japanese Patent Application Laid-open No. 40297/1989) that 3'-fluoro-3'-deoxy as a novel semi-synthetic aminoglycoside antibiotic. Describing the creation of kanamycin A,
In addition, for the production of this new compound, 3-deoxy-3-fluoro-1,2 as a known substance;
A synthetic method has been described starting from 5,6-di-O-isopropylidene-α-D-glucofuranose via a multistep route. Furthermore, this time, the present inventor has discovered that 3â²-fluoro-3â²-
Research was carried out with the intention of creating deoxykanamycin B. In the method for synthesizing 3'-deoxykanamycin B from kanamycin B, starting from kanamycin B, this is converted into penta-N-
A protected-2â³,4â³,6â³-tri-O-protected-kanamycin B derivative was obtained, the 3â²-hydroxyl group of this derivative was converted to a sulfonic acid ester, and the resulting 3â²-sulfonyloxy group was converted to a sulfonic acid ester. It was possible to produce N,O-protected 3'-iodinated, 3'-brominated or 3'-chloro derivatives of kanamycin B by the action of alkali metal iodides, bromides or chlorides ( (See Japanese Patent Publication No. 57-876, Example 1, and U.S. Pat. No. 3,929,762, as well as JP-A-56-63,993 and U.S. Pat. No. 4,349,666). However, 3â²-
When using an alkali metal fluoride as a halogenating agent, Japanese Patent Publication No. 57-876 and Japanese Patent Application Laid-open No. 56-876
3â²- of Kanamycin B described in Publication No. 63993
Even if the method for preparing iodinated, 3'-brominated or 3'-chloro derivatives is reused, the 3'-
It has been experimentally observed that deoxy-3'-fluorinated derivatives cannot be prepared. Furthermore, it has been well recognized that alkali metal fluorides as nucleophilic reagents differ significantly from other alkali metal halides in terms of reaction behavior. As a result of research, the present inventor found that the N, O -Known substance described as a protected derivative, 6'-N,4'-O-carbonyl-4'',
6â³-O-cyclohexylidene-1,2â²,3,3â³-
Using tetra-N-tosylkanamycin B,
We succeeded in synthesizing 3'-fluoro-3'-deoxykanamycin B for the first time using the synthetic route described below, and this new compound has antibacterial activity against various Gram-positive and -negative bacteria, including resistant bacteria. admitted that. Therefore, the gist of the present invention is that the following formula
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ã€ã·ã³ïŒ¢ã®æèã¹ãã¯ãã«ã第ïŒè¡šã«ç€ºãã3'-Fluoro-3'-deoxykanamycin B and its acid addition salts are represented by: 3'-Fluoro-3'-deoxykanamycin B of the present invention is a white powder that does not have a clear melting point,
It is a basic substance that exhibits the physical properties described in the later examples. The novel compounds of the present invention () are usually obtained as free bases or hydrates or carbonates, but
Any non-toxic acid addition salt can be prepared by conventional methods. Examples of acid addition salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, and organic acids such as acetic acid, malic acid, citric acid, ascorbic acid, and methanesulfonic acid. The 3'-fluoro-3'-deoxykanamycin B or acid addition salt thereof of the present invention can be formulated into an antibacterial composition by combining it with a pharmaceutically acceptable liquid or solid carrier. The antibacterial spectrum (minimum inhibitory concentration) of 3'-fluoro-3'-deoxykanamycin B (abbreviated as 3'-F-kanamycin B) (free base) of the present invention is shown in Table 1 below. For comparison, the antibacterial spectrum of Kanamycin B is also shown in Table 1.
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§ïŒã§ãã次åŒ[Table] As described above, 3'-fluoro-3'-deoxy-kanamycin B of the present invention has a higher resistance to resistant bacteria than kanamycin B. This result holds true for both resistant E. coli and Pseudomonas aeruginosa.
Starting from kanamycin B, we
Research was carried out with the intention of developing a method for producing fluoro-3'-deoxykanamycin B.
As a result, the following findings were obtained and a method for producing 3'-fluoro-3'-deoxykanamycin B was completed. That is, starting from kanamycin B, the following formula, which is known as an N,O-protected derivative of kanamycin B (see JP-A-56-63993 and US Pat. No. 4,349,666):
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ããã«ã¢ããåºã®åœ¢ã«è»¢åããããããŠæ¬¡åŒ[Chemical formula] [In the formula, Ts represents a tosyl group]
6â²-N,4â²-O-carbonyl-4â³,6â³-O-cyclohexylidene-1,2â²,3,3â³-tetra-N-
Tosylkanamycin B [referred to as compound (a)] is prepared and this compound (a) is reacted with 2.5 to 5 molar ratio of N-acetylimidazole in anhydrous dimethyl sulfoxide in the presence of pyridine at a temperature of 0 to 50°C. It was found that only the 2''-hydroxy group of compound (a) can be selectively acetylated without acetylating the 3'-hydroxyl group.The 6'-N,4'- O-carbonyl-4â³,6â³-
O-cyclohexylidene-2â³-O-acetyl-
1,2',3,3''-tetra-N-tosylkanamycin B [referred to as compound (b)] is prepared by treating it with a benzylsulfonylating agent such as benzylsulfonyl chloride, a mesylating agent such as mesyl chloride, or a mesylating agent such as tosyl chloride. When reacted with a tosylating agent in anhydrous pyridine at a temperature below 50°C, the 5-
Almost no hydroxyl group is sulfonylated
that the 3'-hydroxyl group can be substantially selectively sulfonylated;
6â²-N,4â²-O-carbonyl-4â³,6â³-O-cyclohexylidene-2â³-O-acetyl-1,2â²,
3,3â³-tetra-N-tosyl-kanamycin B
[Compound (c)] can be produced, and a benzylsulfonylating agent is most suitable for the selective sulfonylation of the 3'-hydroxyl group of compound (b), and furthermore, when a mesylating agent is used, the compound The 5-hydroxyl group in (b) is also partially sulfonylated, but the resulting 3',5-O-sulfonylated product is converted to the desired mono-3'-O-sulfonyl derivative by chromatography. , that is, it was found that it could be separated from compound (c). Furthermore, this compound
(c) is the reaction temperature from 0°C to the boiling point of methanol, ethanol or benzyl alcohol;
Anhydrous methanol at a concentration of 1 to 5% (by weight) using an alkali metal hydroxide such as sodium hydroxide in a molar ratio of 2 to 10 to compound (c) for a reaction time of 5 minutes to 2 hours or more. Alternatively, when treated in anhydrous ethanol or in the presence of anhydrous benzyl alcohol, the 2''-O-acetyl group of compound (c) is eliminated, and the 3'-sulfonyloxy group and 2'- The reaction with the tosylamino group causes the closure of the atridine ring, and at the same time, compound (c)
One of the bonds of the carbonyl group (O=C) that bridged the 6'-amino group and the 4'-hydroxyl group is cut from the 4'-hydroxyl group and reacts with methanol, ethanol, or benzyl alcohol, and 6 â²â
The amino group is converted into the form of a methoxycarbonylamino group or an ethoxycarbonylamino group or a benzyloxycarbonylamino group, thus giving the formula
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次ã®äžè¬åŒ[Chemical formula] [In the formula, Ts is a tosyl group, and Aâ² is a methoxycarbonyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group] 4â³,
6â³-O-cyclohexylidene 3â²-deoxy-3â²-
epi-2â²,3â²-(N,tosyl)epimino-6â²-N-
It has been found that methoxy (or ethoxy or benzyloxy) carbonyl-1,3,3''-tri-N-tosylkanamycin B [referred to as compound (d)] can be produced. When reacting alkali hydroxides, etc., in anhydrous methanol, anhydrous ethanol, or anhydrous benzyl alcohol, by increasing the reaction temperature, reaction time, working concentration, etc. at which the alkali metal hydroxide acts, etc. When the reaction conditions are made more severe than the appropriate conditions mentioned above, the elimination of the 2â³-O-acetyl group and the 2â²,
Closing of the 3'-atiridine ring occurs, but at the same time, the 4',6'-cyclic carbamate moiety (O=C) from compound (c) decomposes, and the 6'-amino group It becomes unprotected and reacts undesirably with the 3'-O-sulfonyloxy group, adversely affecting subsequent reactions. Furthermore, as a result of repeated experiments and research, the present inventors found that compound (d) was obtained by converting compound (d) into sodium hydrogen difluoride or sodium hydrogen difluoride using a polar organic solvent such as anhydrous dimethylformamide or dimethylacetamide as a reaction medium. When reacted with potassium hydrogen difluoride under heating, for example, at a temperature of 120 to 200°C for a reaction time of, for example, about 10 minutes to about 20 hours, the 2',3'-aziridine ring opens and the 3'-position is fluorinated, therefore
4â³,6â³-O-cyclohexylidene-3â²-fluoro-3â²-deoxy-6â²-N-methoxy (or ethoxy or benzyloxy)carbonyl-1,2â²,
It has been discovered that 3,3''-tetra-N-tosylkanamycin B [referred to as compound (c)] is produced.In this way, along with the opening of the aziridine ring, kanamycin is produced by the alkali metal hydrogen difluoride. As far as the inventors are aware, this is the first finding of an aminoglycoside antibiotic that the 3'-position of Compound B is fluorinated. 1
When treated with a known deprotection method that removes the amino protecting groups at -, 2'-, 3- and 3''-amino groups, the desired 3'-fluoro-3'-deoxykanamycin B (compound) was produced. .On the other hand, compound (d)
It is recognized that the 3'-fluoro-3'-deoxykanamycin B compound cannot be produced if all of the tosyl groups are first eliminated and then reacted with an alkali metal hydrogen difluoride under the conditions described above. Ta. In this way, the inventor has discovered that kanamycin B
We succeeded in developing a route to synthesize 3'-fluoro-3'-deoxykanamycin B starting from 3'-fluoro-3'-deoxykanamycin B. Furthermore, an amino protecting group (methoxycarbonyl group, ethoxycarbonyl group, or benzyloxycarbonyl group) on the 6â²-amino group of compound (d), and a hydroxyl protecting group (cyclohexyloxycarbonyl group) on the 4â³- and 6â³-hydroxyl groups dene group) is removed from compound (d), and the thus obtained 3'-deoxy-3'-epi-2',3'-(N-tosyl)epimino-1,3,
Free 3'-tri-N-tosylkanamycin B
Another type of amino protecting group such as an alkanoyl group (but not of the sulfonyl group type) is introduced into the 6'-amino group, and the N-protected -3'-
The desired N-protected -3'-fluoro-3'- It was confirmed that deoxykanamycin B compound can be produced. Starting intermediate compounds used in the synthetic route described above
In (a), the amino protecting group protecting the 1-, 2â²-, 3- and 3â³-amino groups is a tosyl group and the hydroxyl protecting group protecting the 4â³- and 6â³-hydroxyl groups is a cyclohexyl group. The tosyl group for amino protection was replaced with other known amino protecting groups of the sulfonyl group type that work equally well, and the 4â³- and
An equivalent protected derivative of compound (a), which can be obtained by replacing the cyclohexylidene group at the 6â³-position with other known hydroxyl protecting groups, can also be obtained by performing the same reaction steps as described above. 4â³,6â³-di-O-protected-1,3,3â³-tri-N equivalent to compound (d)
-Sulfonylation protection-3'-deoxy-3'-epi-
It has been found that 6'-N-methoxy (or ethoxy or benzyloxy) carbonyl-2',3'-(N-sulfonylation protected) epimino-kanamycin B can be prepared. The present invention was completed based on the above-mentioned findings. Therefore, the gist of the second invention is as follows:
The following general formula
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åå¿ãããŠæ¬¡ã®äžè¬åŒ[In the formula, A is an amino-protecting group other than a sulfonyl-type amino-protecting group or a hydrogen atom, B is a sulfonyl-type amino-protecting group, and Q is an alkylsulfonyl group or an aralkylsulfonyl group. or an arylsulfonyl group, X and Y are each a hydrogen atom or a monovalent hydroxyl protecting group, or X and Y jointly form one divalent hydroxyl protecting group] The protected derivative of '-deoxy-3'-epi-2',3'-epimino-kanamycin B has the following formula: MeHF 2 () [wherein Me is an alkali metal atom] and an alkali metal hydrogen difluoride and an organic The following general formula is obtained by reacting under heating in a solvent.
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次åŒ[Chemical formula] A 3'-fluoro-3'-deoxykanamycin B compound represented by the formula [wherein A, B, Q, When amino protecting groups (A, B) and (or) hydroxyl protecting groups (X, Y) remain, these protecting groups and sulfonyl groups (Q) are removed by known methods,
The following formula
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åŒA method for producing 3'-fluoro-3'-deoxykanamycin B represented by: In the method of the second invention, the general formula ()
Amino protecting group A in 3'-deoxy-3'-epi-2',3'-epimino-kanamycin B protected derivative
is any known amino protecting group that does not participate in the reaction,
For example, alkanoyl groups such as acetyl group, trifluoroacetyl group, acyl groups such as aroyl group such as benzoyl group, and alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group; benzyloxycarbonyl group, phenethyl group. It can be an aralkyloxycarbonyl group such as an oxycarbonyl group, or an aryloxycarbonyl group such as a phenoxycarbonyl group or a methoxyphenoxycarbonyl group. However, if the group A is a sulfonyl group type such as an alkylsulfonyl group such as a mesyl group or a tosyl group, an arylsulfonyl group, or an aralkylsulfonyl group, undesirable by-products will be produced during the reaction of the alkali metal hydrogen difluoride. The amino protecting group (A) is not of the sulfonyl group type due to concerns. Although the group (A) can be a hydrogen atom, it is preferable that the 6'-amino group of the compound () is protected. 1-, 3- and in the compound of general formula ()
The 3''-amino group is protected with an amino protecting group (B) of the type of an alkylsulfonyl group such as a mesyl group or a trifluoromethylsulfonyl group, an aralkylsulfonyl group such as a benzylsulfonyl group; an arylsulfonyl group such as a tosyl group. The sulfonyl group Q bonded to the nitrogen atom of the 2â²,3â²-atiridine ring is preferably the same sulfonyl group as B. The 4â³-hydroxyl group and
Protecting group (X, Y) that protects the 6â³-hydroxyl group
can be any known monovalent hydroxyl protecting group, including lower alkyl groups, aryl groups such as phenyl groups; alkanoyl groups such as acetyl groups, or aroyl groups such as benzoyl groups.
However, X and Y may jointly be any known divalent group, including a lower alkylidene group such as an isopropylidene group, an aralkylidene group such as a benzylidene group, a cycloalkylidene group such as a cyclohexylidene group, or a tetrahydropyranylidene group. It may form a hydroxyl protecting group. Introduction of these amino-protecting groups and hydroxyl-protecting groups into kanamycin B compounds has been described, for example, in JP-A No. 55
â105699, British Patent No. 2043634B; Japanese Patent Application Publication No. 1983
â68698, U.S. Patent No. 4357466; Japanese Patent Application Publication No. 1983-
This can be accomplished using conventional protection techniques such as those described in US Pat. No. 152,497 and US Pat. No. 4,359,572. In the second method of the present invention, the alkali metal hydrogen difluoride () to be reacted with the N,O-protected 2',3'-epiminated kanamycin B compound of the general formula () is NaHF 2 , KHF 2 or LiHF2 , but KHF2 is preferred. This reaction may be carried out in a dry organic solvent suitable for the reaction, but is preferably carried out in a polar organic solvent such as dimethylformamide, dimethylacetamide, acetonitrile or sulfolane. Dimethylformamide is most suitable. Depending on the type of organic solvent used, the desired reaction may not proceed. The reaction is carried out under heating, and the reaction temperature is suitably in the range of 120 to 200°C. Preferably, the temperature is within the range of 150 to 160°C. The above reaction produces a 3'-fluoro-3'-deoxy-kanamycin B protected derivative of the general formula (), which can be collected by extracting the reaction solution with a suitable organic solvent such as ethyl acetate, and then extracting it with silica gel. This can be carried out by separation and purification using column chromatography. If an amino protecting group and/or a hydroxyl protecting group remain in the compound of general formula (),
The protecting group is removed in the deprotection step. This deprotection step is carried out in stages depending on the type of protecting group used, using a commonly used deprotection method and a known method, such as the method disclosed in the above-mentioned Japanese Patent Application Laid-Open No. It can be done. The reaction solution obtained in this deprotection reaction is concentrated, and the solid residue is dissolved in water, passed through a CM-Sephadex C-25 column, and developed with aqueous ammonia to isolate and purify the desired product. 3'-fluoro-3'-deoxykanamycin B [compound ()] can be obtained. The gist of the third invention is the following general formula
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å¿ãããŠæ¬¡ã®äžè¬åŒ[Formula, B is a sulfonyl group-type amino protecting group, X and Y are each a hydrogen atom or a monovalent hydroxyl protecting group, or X and Y are jointly one 2 forming a valent hydroxyl protecting group,
Q is the same alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group as B,
Z is the same or different alkylsulfonyl group as Q,
3'-O-sulfonyl-6'-, which is an aralkylsulfonyl group or an arylsulfonyl group, and V is a hydroxyl protecting group or a hydrogen atom.
The protected derivative of N,4'-O-carbonyl-kanamycin B is reacted with an alkali metal hydroxide in the presence of methanol, ethanol or benzyl alcohol to form the following general formula:
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åå¿ãããŠæ¬¡ã®äžè¬åŒ[In the formula, B, X, Y, Q and V have the same meanings as above, and A' is an amino protecting group in the form of a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group] 3'-deoxy-3'-epi-2',3'-epimino-6'-N-
Either a protected derivative of alkoxy- or araloxy-carbonyl-kanamycin B is generated and then a compound of formula (') is used immediately, or a compound of formula (') is formed with a hydroxyl protecting group (V,
3â²- obtained by eliminating part or all of X, Y)
Deoxy-3'-epi-2',3'-epimino-6'-N
-Using a protected kanamycin B compound, it is reacted with an alkali metal hydrogen difluoride of the following formula MeHF 2 () [wherein Me is an alkali metal atom] under heating in an organic solvent to form the following general formula
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ãšãç¹åŸŽãšããã次åŒ[In the formula, A' is an amino-protecting group in the form of a methoxycarbonyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group, B is the same amino-protecting group as above, and V, X' and Y' are The above V,
have the same meaning as X and Y, or
3'-fluoro-3'-deoxykanamycin B compound represented by When the hydroxyl protecting groups (X, Y) remain, these protecting groups and the sulfonyl group (Q) are removed by a known method.
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ãååç©(b)ãšãããã®çæA method for producing 3'-fluoro-3'-deoxykanamycin B represented by: In the third method of the present invention, 3'-O-sulfonyl- of the general formula (V) used as a starting compound
The amino protecting group B and the hydroxyl protecting groups X and Y in the 6â²-N,4â²-O-carbonyl-kanamycin B protected derivative are each represented by the general formula () used as the starting compound in the second method of the present invention. of
The amino protecting group B and the hydroxyl protecting groups X and Y, respectively, in the 3'-deoxy-3'-epi-2',3'-epimino-kanamycin B protected derivative may be the same. 3'-O-sulfonyl group (Z)
can be an alkylsulfonyl group having 1 to 4 carbon atoms, such as a methanesulfonyl group (mesyl group), an ethanesulfonyl group; an aralkylsulfonyl group, such as a benzylsulfonyl group; an arylsulfonyl group, such as a tosyl group, but is a benzylsulfonyl group. is preferable. The reaction of the 3'-O-sulfonyl-kanamycin B derivative of general formula () with an alkali metal hydroxide such as sodium hydroxide in the presence of methanol or ethanol or benzyl alcohol is carried out under anhydrous conditions. Alkali metal hydroxide is kanamycin B
It is preferably used in a molar ratio of 2 to 10 per mole of compound () and in a concentration of 1 to 5% by weight in the reaction medium. The reaction temperature can range from 0°C to the reflux temperature of the reaction medium. The reaction time may be at least 5 minutes, and even if the reaction time is prolonged, undesirable by-products will not be produced as much, but the desired 2',3'-epimination product (') will be bonded to the 6'-amino group of the product ('). It is preferable to use reaction conditions that do not eliminate the methoxycarbonyl group, ethoxycarbonyl group, etc. (A'). In the third method of the present invention, the step of reacting the 2',3'-epimination product of the general formula (') produced as an intermediate with the alkali metal hydrogen difluoride of the formula (), and thereafter The step of deprotecting the 3'-fluoro-3'-deoxykanamycin B compound of general formula ('), which is carried out as necessary, can be carried out in the same manner as the corresponding step in the second method of the present invention. Next, the present invention will be explained with reference to reference examples and examples. In the formulas shown in these examples, Ac represents an acetyl group, Ts represents a tosyl group, Bes represents a benzylsulfonyl group, Cbm represents a methoxycarbonyl group, Tfl represents a trifluoromethanesulfonyl group, and Ms represents a mesyl group. Reference example 1 2â³-O-acetyl-4â²-O, 6â²-N-carbonyl-4â³, 6â³-O-cyclohexylidene-1,
Production of 3,2â²,3â³-tetra-N-tosylkanamycin B [referred to as compound (b)]
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ïŒ[Chemical formula] 6â²-N,4â²-O-carbonyl-4â³,6â³-O-cyclohexylidene-1,2â²,3,3â³-tetra-N
- 1.58 g of tosylkanamycin B [i.e., compound (a) above] was dissolved in 7.9 ml of a mixture of anhydrous dimethyl sulfoxide and pyridine (9:1), and N-
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1.6 g of (b) was obtained. Reference example 2 2â³-O-acetyl-3â²-O-benzylsulfonyl-4â²-O-6â²-N-carbonyl-4â³,6â³-O
-Cyclohexylidene-1,3,2',3''-tetra-N-tosylkanamycin B [Compound (c-
1) Generation of
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ïŒïœâïŒïŒãšãããã®çæ[Chemical formula] 115 mg of compound (b) obtained in Reference Example 1 was dissolved in 2 ml of anhydrous pyridine, 27 mg of benzylsulfonyl chloride was added, and the mixture was reacted at -20°C for 5 hours to form 3'-O-benzylsulfonylation. After adding a small amount of water (0.02 ml), the reaction solution was concentrated, and the residue was washed with a large amount of water and dried to obtain the title compound (c) as a colorless solid.
125 mg of -1) was obtained. Example 1 (a) 4â³,6â³-O-cyclohexylidene-3â²-deoxy-3â²-epi-6â²-N-methoxycarbonyl-1,3,3â³-tri-N-tosyl-2 â²,3â²â(N
-Tosyl) production of epiminokanamycin B [referred to as compound (d-1)]
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çæ[Chemical formula] 140 mg of compound (c-1) obtained in Reference Example 2
was dissolved in 3.2 ml of anhydrous methanol containing 0.5 M sodium hydroxide, and reacted at room temperature for 3 hours.
The reaction solution was neutralized with 1M hydrochloric acid and concentrated, and the residue was washed with a large amount of water and dried to obtain 117 mg of the title compound (d-1) as a colorless solid. (b) 4â³,6â³-O-cyclohexylidene-3â²-deoxy-3â²-fluoro-6â²-N-methoxycarbonyl-1,3,2â²,3â³-tetra-N-tosylkanamycin BB Production of [referred to as compound (e-1)]
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ã§åŠçããŠèª¿è£œãããŠäžã€äžèšã®åŒ[Chemical value] 116.4 mg of compound (d-1) obtained in the previous section (a)
was dissolved in 2.3 ml of dimethylformamide, 37 mg of potassium hydrogen fluoride (KHF 2 ) was added, and the mixture was reacted at 150° C. for 2 hours with stirring. The reaction solution was cooled and poured into 47 ml of saturated sodium bicarbonate solution, and the precipitate was collected and washed with water. This was subjected to silica gel column chromatography (6 g of Wako Gel C-200, developed with chloroform-methanol (30:1)) to obtain crude compound (e-1) as a pale yellow solid containing compound (c-1) as the main component. 75.7 mg of Although this substance could not be separated into its respective mixed components,
In the 19 F NMR spectrum (in deuterated pyridine, CFCl 3 internal standard), a clear double triplet originating from 3'-F (J F,H-3 55H 2 , J F,H-2
ïŒJ F,H-4 ïŒ12H 2 ) was recognized. (c) Production of 3'-fluoro-3'-deoxy-kanamycin B (compound) About 140 mg of metallic sodium was added to about 23 ml of liquid ammonia cooled to -50°C to obtain a blue solution.
To this, 75.7 mg of crude compound (e-1) (product of the previous item (b)) was dissolved in 2.3 ml of tetrahydrofuran.
After stirring at the same temperature for 5 minutes, methanol was added to obtain a colorless solution (tosyl group eliminated). After evaporating ammonia and methanol, the residue was dissolved in 6 ml of water.
Heated at 80°C for 1 hour. Hydrolysis occurred due to the action of the generated sodium hydroxide, and the methoxycarbonyl group was eliminated. 10 ml of Dowex 50W x 2 (H + type) resin was added to the reaction solution, and the resin was adsorbed thereon and left overnight (elimination of cyclohexylidene group). The resulting deprotected product was added together with the resin to the top of a column containing 3 ml of the same resin, washed with water, and eluted with 1N aqueous ammonia to collect the ninhydrin-positive portion. The obtained product is further
CM-Sephadex C-25 (NH + 4
type) column with ammonia water as a developing agent (0.05â
0.15N), and the portion containing 3'-fluoro-3'-deoxy-kanamycin B was collected and concentrated. Pure 3'-fluoro-3'-deoxykanamycin B was obtained as 9.8 mg of white powder. Compound (d)
The yield is about 19%. Optical rotation: [α] 22 D +125° (c0.6, water) 1 H-NMR data (in 20% ND 3 , D 2 O): ÎŽ447 (double triplet, H-3â², J F,H- 3 54H 2 ,
J F, H-2 = J F, H-4 = 10H 2 ), 5.03 (double, H-
1â³, J 1 â³ , 2 â³3.8H 2 ), 5.34 (triplet, H-1â²
ïŒ
J1 ' ,2 '= J1 ' ,F-3 =3.8H2 ) Example 2 (a) 3'-O-benzylsulfonyl-4'-0,6'-
N-carbonyl-4â³,6â³-O-cyclohexylidene-1,3,2â²,3â³-tetra-N-tosylkanamycin B [referred to as compound (c-2)] (Journal of the Chemical Society of Japan 1982 mentioned above) 10, p. 1707) was dissolved in 2.7 ml of anhydrous methanol containing 0.5 M sodium hydroxide and left to react at room temperature for 3 hours.Then, the reaction was carried out in the same manner as in Example 1 (a). The solution was treated to obtain 116 mg of compound (d-1). (b) 55 mg of compound (d-1) obtained in the previous section (a) was dissolved in 1 ml of dimethylformamide, and dissolved in sodium hydrogen fluoride (NaHF). Add 15mg of 2 ) and heat to 150â.
The mixture was stirred for 2 hours. Thereafter, it was treated in the same manner as in Example 1 (b) to obtain 36 mg of crude compound (e-1). This crude compound (e-1) was treated in the same manner as in Example 1 (c) to obtain 3'-fluoro-3'-deoxykanamycin B. Example 3 (a) 4â³,6â³-O-isopropylidene-6â²-N-benzyloxycarbonyl-1,3,2â²,3â³-tetra-N-benzylsulfonyl-3â²-fluoro-3â² -deoxy-kanamycin B [compound (e
-2)] 3â²-O-benzylsulfonyl-4â²-O,6â²-N
-Carbonyl-4â³,6â³-O-isopropylidene-
1,3,2',3''-tetra-N-benzylsulfonylkanamycin B [referred to as compound (c-2)] is prepared by treating with sodium hydroxide in the presence of benzyl alcohol and has the following formula:
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2',3'-(N-benzylsulfonyl)epimino-
3â²-deoxy-3â²-epi-4â³,6â³-O-isopropylidenekanamycin B [compound (d-2) 80
mg was dissolved in 1.5 ml of dimethylformamide, 25 mg of potassium hydrogen fluoride was added, and the mixture was stirred at 150° for 2 hours to react. The reaction solution was then treated in the same manner as in Example 1 (b) to obtain 44 mg of the crude title compound (e-2).
I got it. (b) 3'-Fluoro-3'-deoxykanamycin B
Formation of the crude product from the previous section (a) in 1.5% tetrahydrofuran
ml, and the solution was added to a solution that turned blue by adding about 80 mg of metallic sodium to about 15 ml of liquid ammonia cooled to -50°C. After reacting for 5 minutes (elimination of benzylsulfonyl group and benzyloxycarbonyl group), methanol was added to stop the reaction. After evaporating the ammonia and methanol, the residue is dissolved in water and added to Dowex.
5 ml of 50W x 2 (H + type) resin was added to adsorb the product and left overnight (isopropylidene group elimination). The resulting deprotected product was added to the top of a 2 ml column containing the same resin, washed with water, and eluted with 1N aqueous ammonia to collect the ninhydrin-positive portion. Thereafter, CM-
Purification with a Sephadex column yielded 4.7 mg of 3'-fluoro-3'-deoxykanamycin B. Example 4 (a) 4â³,6â³-O-cyclohexylidene-6â²-N-
Production of methoxycarbonyl-1,3-2',3''-tetra-N-trifluoromethanesulfonyl-3'-fluoro-3'-deoxykanamycin B [referred to as compound (e-3)] 3'-O-benzylsulfonyl â4â²âO,6â²âN
-Carbonyl-4â³,6â³-O-cyclohexylidene-1,3,2â²,3â³-tetra-N-trifluoromethanesulfonylkanamycin B [Compound (c-3)
] with sodium hydroxide in anhydrous methanol and has the following formula:
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3'-Deoxy-3'-epi-6'-N-methoxycarbonyl-1,3,3''-tri-N-trifluoromethanesulfonyl-2',3'-(N-trifluoromethanesulfonyl)epiminokanamycin B 110 mg of [compound (d-3)] was dissolved in 2.5 ml of dimethylformamide. 40 mg of potassium hydrogen fluoride was added to this solution and stirred at 150°C for 2 hours to react.The reaction solution was used as Example 1. By treating in the same manner as in (B), 72 mg of the crude title compound (e-3) was obtained. (B) 3'-Fluoro-3'-deoxykanamycin B
Production of the crude product from the previous section (a) was dissolved in 5 ml of 0.6M sodium hydroxide solution, and the solution was heated at 80°C for 1 hour. This operation removed the trifluoromethanesulfonyl group and the methoxycarbonyl group. Dowex 50W x 2 (H + type) resin 8 in the reaction solution
ml was added thereto, and the product was adsorbed thereto and left overnight (cyclohexylidene group eliminated). The deprotected product was added to the top of a 3 ml column containing the same resin, washed with water, and eluted with 1N aqueous ammonia to collect the ninhydrin-positive portion. When the obtained substance is further purified with CM-Sephadex C-25 (NH 4 + form) as in Example 1 (c),
10 of 3'-fluoro-3'-deoxykanamycin B
I got mg. Example 5 (a) 4â³,6â³-benzylidene-6â²-N-ethoxycarbonyl-3â²-deoxy-3â²-fluoro-1,
Production of 3,2',3''-tetra-N-mesylkanamycin B [referred to as compound (e-4)] 3'-O-benzylsulfonyl-4'-O,6'-N
-carbonyl-4â³,6â³-O-benzylidene-1,
3,2â²,3â³-tetra-N-mesylkanamycin B
It is prepared by treating [referred to as compound (c-4)] with potassium hydroxide in anhydrous ethanol and has the following formula:
ãåã
ã§ç€ºããã4â³ïŒ6â³ââãã³ãžãªãã³â3â²âããª
ãã·â3â²âãšãâ6â²ââãšããã·ã«ã«ããã«â
ïŒïŒïŒïŒ3â³âããªââã¡ã·ã«â2â²ïŒ3â²âïŒïŒ®âã¡
ã·ã«ïŒãšãããã«ããã€ã·ã³ïŒ¢ãååç©ïŒïœâïŒïŒ
ãšãããã®45mgããžã¡ãã«ãã«ã ã¢ããã®1.1ml
ã«æº¶è§£ããããåæ°ŽçŽ ã«ãªãŠã 18mgãå ãã150
âã§ïŒæéæªæããŠåå¿ãããããã®åå¿æ¶²ã以
åŸãå®æœäŸïŒ(ã)ãšåæ§ã«åŠçãããšãè¡šé¡ååç©
ïŒïœ
âïŒïŒã®ç²è£œç©ã®28mgãåŸãã
(ã) 3â²âãã«ãªãâ3â²âããªãã·ã«ããã€ã·ã³ïŒ¢
ã®çæ
åé
(ã€)ã®ç²è£œç©ãå®æœäŸïŒ(ã)ãšåæ§ãªæ¹æ³ã§è±
ä¿è·åŠçã粟補ãããšãç®çã®è¡šé¡ååç©ãåŸã
ããã4â³,6â³-O-benzylidene-3â²-deoxy-3â²-epi-6â²-N-ethoxycarbonyl- represented by
1,3,3â³-tri-N-mesyl-2â²,3â²-(N-mesyl)epiminokanamycin B [Compound (d-4)
] 45mg of 1.1ml of dimethylformamide
Add 18 mg of potassium hydrogen fluoride to 150
The mixture was stirred and reacted at â for 2 hours. The reaction solution was then treated in the same manner as in Example 1 (b) to obtain 28 mg of the title compound (e-4) as a crude product. (b) 3'-Fluoro-3'-deoxykanamycin B
Production of the crude product obtained in the previous section (a) was deprotected and purified in the same manner as in Example 1 (c) to obtain the desired title compound.
Claims (1)
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æ±ã®ç¯å²ç¬¬ïŒé ã«èšèŒã®æ¹æ³ã[Scope of Claims] 3'-Fluoro-3'-deoxykanamycin B represented by the following formula: and its acid addition salt. 2 Following general formula group, aralkylsulfonyl group or arylsulfonyl group, and X and Y are each a hydrogen atom or a monovalent hydroxyl protecting group, or X and Y together form a divalent hydroxyl protecting group The protected derivative of 3'-deoxy-3'-epi- 2 ',3'-epimino-kanamycin B represented by A 3'-fluoro- 3'-deoxykanamycin B compound is produced, and when amino protecting groups (A, B) and/or hydroxyl protecting groups (X, Y) remain in the compound of formula (), these protecting groups and characterized by removing the sulfonyl group (Q) by a known method,
A method for producing 3'-fluoro-3'-deoxykanamycin B represented by the following formula: 3. The organic solvent used in the reaction of 3'-deoxy-3'-epi-2',3'-epimino-kanamycin B compound () and alkali metal hydrogen difluoride is dimethylformamide, dimethylacetamide, acetonitrile or sulfolane. Claim 2
The method described in section. 4. The method according to claim 2, wherein the alkali metal hydrogen difluoride is sodium hydrogen difluoride or potassium hydrogen difluoride. 5 The following general formula: [In the formula, B is a sulfonyl group-type amino protecting group, and X and Y are each a hydrogen atom or a monovalent hydroxyl protecting group, or to form one divalent hydroxyl protecting group,
Q is the same alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group as B,
Z is the same or different alkylsulfonyl group as Q,
3'-O-sulfonyl-6'-, which is an aralkylsulfonyl group or an arylsulfonyl group, and V is a hydroxyl protecting group or a hydrogen atom.
The protected derivative of N,4'-O-carbonyl-kanamycin B is reacted with an alkali metal hydroxide in the presence of methanol or ethanol or benzyl alcohol to form the following general formula [where B, X, Y, 3'-deoxy-3'-epi-2' where Q and V have the same meanings as above and A' is an amino protecting group in the form of a methoxycarbonyl group or an ethoxycarbonyl group or a benzyloxycarbonyl group. ,3'-epimino-6'-N-
Either a protected derivative of alkoxy- or aralkyloxy-carbonyl-kanamycin B is generated and then a compound of formula (') is used immediately, or a compound of formula (') is formed with a hydroxyl protecting group (V,
3â²- obtained by eliminating part or all of X, Y)
Deoxy-3'-epi-2',3'-epimino-6'-N
-Using a protected kanamycin B compound, it is reacted with an alkali metal hydrogen difluoride of the following formula MeHF 2 () [wherein Me is an alkali metal atom] under heating in an organic solvent to form the following general Formula: [wherein A' is an amino-protecting group in the form of a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group, B is the same amino-protecting group as above, and V, X' and Y' is the above V,
have the same meaning as X and Y, or
3'-fluoro-3'-deoxykanamycin B compound represented by When the hydroxyl protecting groups (X, Y) remain, these protecting groups and the sulfonyl group (Q) are removed by a known method. Method for producing 3'-deoxykanamycin B. 6 The organic solvent used for the reaction of 3'-deoxy-3'-epi-2',3'-epimino-kanamycin B compound (') and alkali metal hydrogen difluoride is dimethylformamide, dimethylacetamide, acetonitrile or sulfolane. A method according to certain claim 5. 7. The method according to claim 5, wherein the alkali metal hydrogen difluoride is sodium hydrogen difluoride or potassium hydrogen difluoride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59262700A JPS61140597A (en) | 1984-12-14 | 1984-12-14 | 3'-fluoro-3'-deoxykanamycin b, and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59262700A JPS61140597A (en) | 1984-12-14 | 1984-12-14 | 3'-fluoro-3'-deoxykanamycin b, and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61140597A JPS61140597A (en) | 1986-06-27 |
| JPH0582395B2 true JPH0582395B2 (en) | 1993-11-18 |
Family
ID=17379378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59262700A Granted JPS61140597A (en) | 1984-12-14 | 1984-12-14 | 3'-fluoro-3'-deoxykanamycin b, and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61140597A (en) |
-
1984
- 1984-12-14 JP JP59262700A patent/JPS61140597A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61140597A (en) | 1986-06-27 |
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