JP6845099B2 - マクロライド系抗菌剤の調製プロセス - Google Patents
マクロライド系抗菌剤の調製プロセス Download PDFInfo
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- JP6845099B2 JP6845099B2 JP2017124117A JP2017124117A JP6845099B2 JP 6845099 B2 JP6845099 B2 JP 6845099B2 JP 2017124117 A JP2017124117 A JP 2017124117A JP 2017124117 A JP2017124117 A JP 2017124117A JP 6845099 B2 JP6845099 B2 JP 6845099B2
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- 239000003120 macrolide antibiotic agent Substances 0.000 title description 22
- 238000002360 preparation method Methods 0.000 title description 16
- 239000003242 anti bacterial agent Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 202
- 239000000203 mixture Substances 0.000 claims description 35
- AMKPQMFZCBTTAT-UHFFFAOYSA-N 3-ethylaniline Chemical compound CCC1=CC=CC(N)=C1 AMKPQMFZCBTTAT-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 description 55
- 230000008569 process Effects 0.000 description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- -1 4-nitrophenylacetyl Chemical group 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 125000002252 acyl group Chemical group 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 30
- 229910052739 hydrogen Inorganic materials 0.000 description 28
- 239000001257 hydrogen Substances 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 238000004519 manufacturing process Methods 0.000 description 26
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 25
- 125000003118 aryl group Chemical group 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 125000001072 heteroaryl group Chemical group 0.000 description 19
- 150000002772 monosaccharides Chemical class 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 18
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 150000002431 hydrogen Chemical class 0.000 description 14
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 12
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 125000003710 aryl alkyl group Chemical group 0.000 description 12
- 150000001540 azides Chemical class 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 235000000346 sugar Nutrition 0.000 description 11
- 229910052720 vanadium Inorganic materials 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 10
- 229940041033 macrolides Drugs 0.000 description 10
- ZOYWWAGVGBSJDL-UHFFFAOYSA-N D-desosamine Natural products CC1CC(N(C)C)C(O)C(O)O1 ZOYWWAGVGBSJDL-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- VTJCSBJRQLZNHE-CSMHCCOUSA-N desosamine Chemical compound C[C@@H](O)C[C@H](N(C)C)[C@@H](O)C=O VTJCSBJRQLZNHE-CSMHCCOUSA-N 0.000 description 9
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 9
- 125000004404 heteroalkyl group Chemical group 0.000 description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 8
- 125000002877 alkyl aryl group Chemical group 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- 239000004202 carbamide Substances 0.000 description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
- 229960002626 clarithromycin Drugs 0.000 description 8
- 150000004676 glycans Chemical class 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 229920001282 polysaccharide Polymers 0.000 description 8
- 239000005017 polysaccharide Substances 0.000 description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 7
- 230000003213 activating effect Effects 0.000 description 7
- 125000000732 arylene group Chemical group 0.000 description 7
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000002993 cycloalkylene group Chemical group 0.000 description 7
- 229910052721 tungsten Inorganic materials 0.000 description 7
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000003463 adsorbent Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 239000012025 fluorinating agent Substances 0.000 description 6
- 239000007800 oxidant agent Substances 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000002016 disaccharides Chemical class 0.000 description 5
- 239000003835 ketolide antibiotic agent Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 230000001590 oxidative effect Effects 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 4
- LFMZGBHJJNIRKH-UHFFFAOYSA-N 4-azidobutan-1-amine Chemical compound NCCCCN=[N+]=[N-] LFMZGBHJJNIRKH-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000001345 alkine derivatives Chemical class 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000012973 diazabicyclooctane Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical compound NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 208000022362 bacterial infectious disease Diseases 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229960003276 erythromycin Drugs 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 150000002596 lactones Chemical group 0.000 description 3
- 244000000010 microbial pathogen Species 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 2
- AZWIJYAGFOFYIL-UHFFFAOYSA-N 1,4-diazidobutane Chemical compound [N-]=[N+]=NCCCCN=[N+]=[N-] AZWIJYAGFOFYIL-UHFFFAOYSA-N 0.000 description 2
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical group CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 238000005675 Corey-Kim oxidation reaction Methods 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-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
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 208000010362 Protozoan Infections Diseases 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000005001 aminoaryl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
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- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
R1は単糖類または多糖類であり;
Aは、−CH2−、−C(O)−、−C(O)O−、−C(O)NH−、−S(O)2−、−S(O)2NH−、または、−C(O)NHS(O)2−であり;
Bは−(CH2)n−であって、式中、nは、0から10までの整数であるか、あるいは、Bは、任意のアルケニル基またはアルキニル基を含有し得る、2個〜10個の炭素の不飽和炭素鎖であり;
Cは、水素、ハロゲン、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アミノアリール、アルキルアミノアリール、アシル、アシルオキシ、スルホニル、尿素(ureyl、ウレイルともいう。以下に同じ。)およびカルバモイル(これらのそれぞれが任意に置換される)から、それぞれの場合において独立して選択される1個または2個の置換基を表し;
Vは、−C(O)−、−C(=NR11)−、−CH(NR12R13)−または−N(R14)CH2−であり;式中、R11はヒドロキシまたはアルコキシであり、R12およびR13はそれぞれが独立して、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、ジメチルアミノアルキル、アシル、スルホニル、尿素およびカルバモイルから選択され;かつ、R14は、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、ジメチルアミノアルキル、アシル、スルホニル、尿素またはカルバモイルであり;
Wは、水素、F、Cl、Br、IまたはOHであり;かつ、
Xは水素であり;かつ、YはOR7であり;式中、R7は、水素、アミノ糖またはハロ糖を含む単糖類もしくは二糖類、アルキル、アリール、ヘテロアリール、例えば4−ニトロフェニルアセチルおよび2−ピリジルアセチルなどのアシル、または−C(O)NR8R9であり、式中、R8およびR9はそれぞれが独立して、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、ジメチルアミノアルキル、アシル、スルホニル、尿素およびカルバモイルから選択され;あるいは、XおよびYは、結合する炭素と一緒になって、C=Oを形成する)。
R1は単糖類または多糖類であり;
Aは、−CH2−、−C(O)−、−C(O)O−、−C(O)NH−、−S(O)2−、−S(O)2NH−、または、−C(O)NHS(O)2−であり;
Bは−(CH2)n−であって、式中、nは、0から10までの整数であるか、あるいは、Bは、任意のアルケニル基またはアルキニル基を含有し得る、2個〜10個の炭素の不飽和炭素鎖であり;
Cは、水素、ハロゲン、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アミノアリール、アルキルアミノアリール、アシル、アシルオキシ、スルホニル、尿素およびカルバモイル(これらのそれぞれが任意に置換される)から、それぞれの場合において独立して選択される1個または2個の置換基を表し;
Vは、−C(O)−、−C(=NR11)−、−CH(NR12R13)−または−N(R14)CH2−であり;式中、R11はヒドロキシまたはアルコキシであり、R12およびR13はそれぞれが独立して、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、ジメチルアミノアルキル、アシル、スルホニル、尿素およびカルバモイルからなる群から選択され;R14は、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、アルコキシ、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、ジメチルアミノアルキル、アシル、スルホニル、尿素またはカルバモイルであり;
Wは、水素、F、Cl、Br、IまたはOHであり;
Xは水素であり;かつ、YはOR7であり;式中、R7は、水素、アミノ糖またはハロ糖を含む単糖類もしくは二糖類、アルキル、アリール、ヘテロアリール、例えば4−ニトロ−フェニルアセチルおよび2−ピリジルアセチルなどのアシル、または−C(O)NR8R9であり、式中、R8およびR9はそれぞれが独立して、水素、ヒドロキシ、アルキル、アラルキル、アルキルアリール、ヘテロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、ジメチルアミノアルキル、アシル、スルホニル、尿素およびカルバモイルから選択され;あるいは、XおよびYは、結合する炭素と一緒になって、C=Oを形成する)。
本出願は、米国仮特許出願第60/982,446号(2007年10月25日出願、その開示は本明細書により参照によって本明細書中に組み込まれる)の、米国特許法第119条(e)項による利益を主張する。
125mLの酢酸エチルを、25gのクラリスロマイシンAに加えた。26.5gの安息香酸無水物、5.7gの4−ジメチルアミノピリジンおよび6.7gのトリエチルアミンを、25℃〜35℃で反応混合物に加えた。反応混合物を、室温で約70時間撹拌した。反応完了後、酢酸エチルを留去して、表題化合物を得た。
ジメチルホルムアミド(DMF、100mL)を、2’,4’’−ジ−O−ベンゾイル−6−O−メチルエリスロマイシンAに25℃〜35℃で加え、その後、1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン(DBU、6.4g)を反応混合物に加え、室温で撹拌した。1,1’−カルボニルジイミダゾール(CDI、17g)を反応混合物に加え、反応が完了するまで室温で撹拌した。表題化合物が、水の添加、および、生じた沈殿物を回収することによって単離される。
−(4−アジドブチル)−6−O−メチルエリスロマイシンA11,12−環状カルバメートの調製。
DMF(50mL)を、10,11−アンヒドロ−2’,4’’−ジ−O−ベンゾイル−12−O−イミダゾリルカルボニル−6−O−メチルエリスロマイシンA(10g)に25℃〜35℃で加えた。4−アジドブチルアミン(4.4g)およびDBU(1.5g)を反応混合物に加え、その後、反応混合物を、反応が完了するまで25℃〜35℃で撹拌した。その後、反応混合物を冷水で処理し、生じた固体沈殿物を回収した。固体をジクロロメタンで処理し、続いて、抽出および溶媒除去を行うことによって、表題化合物を得た。4−アジドブチルアミン対10,11−アンヒドロ−2’,4’’−ジ−O−ベンゾイル−12−O−イミダゾリルカルボニル−6−O−メチルエリスロマイシンAのモル当量比は、約4:1から約3:1までであるように、任意に選択される。DBU対10,11−アンヒドロ−2’,4’’−ジ−O−ベンゾイル−12−O−イミダゾリルカルボニル−6−O−メチルエリスロマイシンAのモル比は、約1:1から約0.75:1までであるように、任意に選択される。
アセトン(10mL)を、2’,4’’−ジ−O−ベンゾイル−11−N−(4−アジドブチル)−6−O−メチルエリスロマイシンA11,12−環状カルバメート(5g)に加えて、透明な溶液を25℃〜35℃で得た。希HCl(10mL)を反応混合物に加え、反応混合物を室温で24時間撹拌した。反応完了後、反応混合物を酢酸エチルにより抽出し、水酸化ナトリウム溶液で処理することによって、表題化合物を得た。
ジクロロメタン(50mL)を、N−クロロスクシンイミド(2g)に窒素下において室温で加え、0℃に冷却した。ジメチルスルフィド(1.8mL)を、撹拌下、0℃で反応混合物にゆっくり加えた。ジクロロメタン(20mL)に溶解された11−N−(4−アジドブチル)−5−(2’−ベンゾイルデソサミニル)−3−ヒドロキシ−6−O−メチルエリスロノリドA11,12−環状カルバメート(5g)を、撹拌下、0℃で反応混合物に滴下して加えた。反応混合物を約−20℃に冷却し、トリエチルアミン(4mL)をジクロロメタン(5mL)に溶解させた溶液を反応混合物に加え、30分間撹拌した。反応完了後、反応混合物を飽和重炭酸ナトリウム溶液で処理し、有機層を単離した。溶媒の留去によって、表題化合物を得た。さらなる反応条件が、Plataらによって、Tetrahedron、60(2004)、10171〜10180に記載される(その開示全体が参照によって本明細書中に組み込まれる)。
11−N−(4−アジドブチル)−5−(2’−ベンゾイルデソサミニル)−3−ヒドロキシ−6−O−メチルエリスロノリドA11,12−環状カルバメート(100g、0.1225モル)の、Dess−Martinペルヨージナン(170g、0.400モル)による酸化を、ジクロロメタン中、10℃〜15℃で行った。反応混合物を20℃〜25℃で2時間撹拌した。反応混合物を5%水酸化ナトリウム水溶液で処理し、反応を停止させた。有機層を、水および塩化ナトリウム飽和溶液により洗浄した。有機層の蒸留によって溶媒を取り除き、ジイソプロピルエーテルおよびヘキサンの混合物から生成物を単離した。分離された固体をろ過し、真空下、30℃〜35℃で乾燥することによって、表題化合物を得た。Dess−Martinペルヨージナン対11−N−(4−アジドブチル)−5−(2’−ベンゾイルデソサミニル)−3−ヒドロキシ−6−O−メチルエリスロノリドA11,12−環状カルバメートのモル当量比は、任意に、約3.3:1から約1.3:1までである。
11−N−(4−アジドブチル)−5−(2’−ベンゾイルデソサミニル)−3−オキソ−6−O−メチルエリスロノリドA11,12−環状カルバメート(5g)をテトラヒドロフラン(400mL)に溶解した溶液に、7.3mLのカリウムtert−ブトキシドを加え、続いて、2gのN−フルオロベンゼンスルホンイミドを加えた。約1時間後、反応混合物を水で処理することによって反応を停止させ、続いて、ジクロロメタンにより抽出した。有機層を分離し、濃縮することによって、表題化合物を得た。
11−N−(4−アジドブチル)−5−(2’−ベンゾイルデソサミニル)−3−オキソ−6−O−メチルエリスロノリドA11,12−環状カルバメート(100g)をテトラヒドロフラン(2200mL)に溶解した溶液に、カリウムtert−ブトキシド(28g)を−20℃〜−5℃で加え、続いて、N−フルオロベンゼンスルホンイミド(54g)を加えた。約1時間後、反応混合物を5%重炭酸ナトリウム水溶液で処理することによって反応を停止させた。分離された有機層を、水および飽和塩化ナトリウム溶液により洗浄した。溶媒を蒸留によって取り除き、残留物をイソプロピルアルコールおよび水の混合物から結晶化し、ろ過し、そして、真空下、40℃〜45℃で乾燥することによって、表題化合物を得た。N−フルオロベンゼンスルホンイミド対11−N−(4−アジドブチル)−5−(2’−ベンゾイルデソサミニル)−3−オキソ−6−O−メチルエリスロノリドA11,12−環状カルバメートのモル当量比は、任意に、約1.6:1から約1.2:1までである。溶媒(mL)対11−N−(4−アジドブチル)−5−(2’−ベンゾイルデソサミニル)−3−オキソ−6−O−メチルエリスロノリドA11,12−環状カルバメートの比は、任意に、約22:1から約17:1までである。
11−N−(3−アミノ−フェニル−1−イルメチル−[1,2,3]−トリアゾール−1−イル]ブチル)−5−(2’−ベンゾイルデソサミニル)−3−オキソ−2−フルオロ−6−O−メチルエリスロノリドA,11,12−環状カルバメート(10g)、3−エチニルフェニルアミン(2.11g)、ヨウ化銅(0.3g)およびジイソプロピルエチルアミン(15.5g)をアセトニトリル(200mL)に加え、室温で20時間撹拌した。反応完了後、反応混合物を希HClで処理することによって反応を停止させ、ジクロロメタンにより抽出した。有機層を重炭酸塩溶液で中和し、乾燥し、そして、濃縮することによって、表題化合物を得た。
11−N−(3−アミノ−フェニル−1−イルメチル−[1,2,3]−トリアゾール−1−イル]ブチル)−5−(2’−ベンゾイルデソサミニル)−3−オキソ−2−フルオロ−6−O−メチルエリスロノリドA,11,12−環状カルバメート(100g)、3−エチニルフェニルアミン(20g)、ヨウ化銅(10g)およびジイソプロピルエチルアミン(155g)をアセトニトリル(600mL)に加え、25℃〜30℃で12時間撹拌した。3−エチニルフェニルアミン対11−N−(3−アミノ−フェニル−1−イルメチル−[1,2,3]−トリアゾール−1−イル]ブチル)−5−(2’−ベンゾイルデソサミニル)−3−オキソ−2−フルオロ−6−O−メチルエリスロノリドA,11,12−環状カルバメートのモル当量比は、任意に、約1.5:1から約1.2:1までである。反応完了後、反応混合物を希HClに注ぎ、ジイソプロピルエーテルにより抽出した。水層をジクロロメタンにより抽出した。ジクロロメタン層を重炭酸ナトリウム水溶液で中和し、乾燥し(NaSO4)、そして、濃縮することによって、表題化合物を得た。この物質をメタノール(600mL)に加え、得られた混合物を50℃〜55℃で12時間加熱した。溶液を活性炭(10g)で処理し、ろ過し、そして、減圧下で濃縮した。残渣を水およびEtOAcの混合物に溶解した。水相のpHを約3.5に調節した。有機層を分離し、水層を酢酸エチルにより抽出し(2回)、続いて、ジイソプロピルエーテルにより抽出した(2回)。得られた水層をアンモニア水(約4%アンモニアの1000mL)に加えた。析出した固体をろ過によって集め、洗浄液のpHが約7〜8になるまで水により洗浄し、そして、減圧下で乾燥することによって、表題化合物を得た。この物質は、任意に、エタノールから再結晶することによってさらに精製される。
11−N−(3−アミノ−フェニル−1−イルメチル−[1,2,3]−トリアゾール−1−イル]ブチル)−5−(2’−ベンゾイルデソサミニル)−3−オキソ−2−フルオロ−エリスロノリドA,11,12−環状カルバメート(6g)をメタノール(60mL)に溶解し、還流下で7時間加熱した。反応完了後、反応混合物を濃縮し、ジイソプロピルエーテル(30mL)により希釈し、そして、室温で2時間撹拌した。得られた固体をろ過によって集めた。この固体は、沈降、結晶化またはクロマトグラフィーによって、任意に精製される。この物質は、酸を加え、引続き、生じた塩を沈殿させることによって、任意に塩に変換される。この物質の分析では、表題化合物が、98%を超える純度を有することが示された。実施例1から実施例8を繰り返すことによって、実施例8の表題化合物の5kgのサンプルを調製した。この多量のサンプルは、約0.1%未満のアミノフェニルエチンまたは約0.07%のアミノフェニルエチンを含有することが明らかになった。
Florisil(21kg)を、63Lの酢酸エチルを含むカラムに詰めた。1.4kgの11−N−(3−アミノ−フェニル−1−イルメチル−[1,2,3]−トリアゾール−1−イル]ブチル)−5−デソサミニル−3−オキソ−2−フルオロ−エリスロノリドA,11,12−環状カルバメートを、14Lの酢酸エチルおよび0.7Lのアセトニトリルに溶解させた溶液を、カラムに通す。溶出液を集める。酢酸エチル(112L)をカラムに通し、溶出液を最初の画分と一緒にする。このプロセスをさらに4回繰り返す。一緒にした溶出液を濃縮し、得られた残渣を、50℃〜55℃に加熱することによって39Lのエチルアルコールに溶解させた。体積を約22Lに減らし、25℃〜30℃に冷却する。溶液を5時間〜6時間、撹拌する。生じる固体を集め、冷エチルアルコールにより洗浄する。湿ったケークを、40℃〜45℃に加熱することによって、酢酸エチル/アセトニトリルの溶液(1kgの湿ったケークあたり15L/0.5L)に溶解する。さらなる酢酸エチル(1kgの湿ったケークあたり20L)を溶液に加える。この溶液をFlorisilのカラム(1kgの湿ったケークあたり15kg)に通す。溶出液を集める。カラムを酢酸エチル(1kgの湿ったケークあたり80L)によりフラッシュ洗浄する。溶出液を集め、最初の溶出液と一緒にする。一緒にした溶出液を濃縮し、得られた残渣を、50℃〜55℃に加熱することによって39Lのエチルアルコールに溶解した。体積を約22Lに減らし、25℃〜30℃に冷却する。溶液を5時間〜6時間、撹拌する。生じる固体を集め、冷エチルアルコールにより洗浄する。フィルターケークを、10℃〜15℃に冷却された50Lの水に加える。濃HCl(0.97L)を10℃〜15℃でゆっくり加えることによって、透明な溶液を得る。その溶液をろ過する。ろ液をアンモニア水溶液(0.79Lのアンモニアを28Lの水に溶解)に10℃〜25℃でゆっくり加える。得られる混合物を30分間撹拌し、固体を遠心分離によって集める。この固体を、水分含有量が1.5%以下になるまで、45℃〜50℃で乾燥した。
1,4−ジブロモブタンを温かいDMFに溶解し、アジ化ナトリウム(3モル当量)で処理した。反応が完了した後、反応混合物を水で希釈し、1,4−ジアジド−ブタンをメチルt−ブチルエーテルに抽出した。トリフェニルホスフィン(1.08モル当量)を、1,4−ジアジド−ブタンの溶液に加えた。反応が完了したとき、反応混合物を、加水分解が完了するまで5%塩酸により希釈した。酸性の水層を分離し、希水酸化ナトリウムで塩基性にした。得られた生成物を、塩化メチレンに抽出した。有機層を分離し、減圧下で濃縮することによって、表題物質を得た。1,4−ジアジド−ブタンの調製は、任意に、約1対3から約1対5までの、アジ化ナトリウムに対するモル当量比を用いて行われる。1,4−ジアジド−ブタンは、任意に、例えば水素化ホウ素ナトリウムである他の還元剤により、4−アジド−ブチルアミンに還元される。
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JP6167095B2 (ja) | 2017-07-19 |
JP2011500834A (ja) | 2011-01-06 |
AU2008316830A1 (en) | 2009-04-30 |
CN105732745A (zh) | 2016-07-06 |
JP5698979B2 (ja) | 2015-04-08 |
CA2703475A1 (en) | 2009-04-30 |
US9453042B2 (en) | 2016-09-27 |
JP2015051994A (ja) | 2015-03-19 |
US20170096445A1 (en) | 2017-04-06 |
CN101917850A (zh) | 2010-12-15 |
JP2017200943A (ja) | 2017-11-09 |
US10131684B2 (en) | 2018-11-20 |
EP2214484A4 (en) | 2013-01-02 |
CN101917850B (zh) | 2016-01-13 |
IL205254A0 (en) | 2010-12-30 |
AU2016203649A1 (en) | 2016-06-16 |
IL205254A (en) | 2017-09-28 |
JP2019147827A (ja) | 2019-09-05 |
HK1226411A1 (zh) | 2017-09-29 |
US20100216731A1 (en) | 2010-08-26 |
WO2009055557A1 (en) | 2009-04-30 |
US20190241602A1 (en) | 2019-08-08 |
AU2008316830B2 (en) | 2016-03-17 |
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