CN116425720A - Preparation method of delafloxacin meglumine - Google Patents
Preparation method of delafloxacin meglumine Download PDFInfo
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- CN116425720A CN116425720A CN202210004950.6A CN202210004950A CN116425720A CN 116425720 A CN116425720 A CN 116425720A CN 202210004950 A CN202210004950 A CN 202210004950A CN 116425720 A CN116425720 A CN 116425720A
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- hydroxyazetidine
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- 229950006412 delafloxacin Drugs 0.000 title claims abstract description 26
- AHJGUEMIZPMAMR-WZTVWXICSA-N 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxoquinoline-3-carboxylic acid;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F AHJGUEMIZPMAMR-WZTVWXICSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- -1 isopropyl anhydride Chemical group 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 11
- 239000012362 glacial acetic acid Substances 0.000 claims description 11
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 9
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 9
- 238000005660 chlorination reaction Methods 0.000 claims description 9
- UDWYGWMSVGVBCG-UHFFFAOYSA-N 2-(dimethylamino)prop-2-enoic acid Chemical compound CN(C)C(=C)C(O)=O UDWYGWMSVGVBCG-UHFFFAOYSA-N 0.000 claims description 8
- GCIUCMRUMOAHKR-UHFFFAOYSA-N 3,5-difluoropyridine-2,6-diamine Chemical compound NC1=NC(N)=C(F)C=C1F GCIUCMRUMOAHKR-UHFFFAOYSA-N 0.000 claims description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 8
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 8
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 claims description 8
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- 125000005907 alkyl ester group Chemical group 0.000 claims description 7
- 239000012320 chlorinating reagent Substances 0.000 claims description 7
- 229960003194 meglumine Drugs 0.000 claims description 7
- 238000005917 acylation reaction Methods 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- UQUPQEUNHVVNKW-UHFFFAOYSA-N azetidin-1-ium-3-ol;chloride Chemical group Cl.OC1CNC1 UQUPQEUNHVVNKW-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- NFTVTXIQFYRSHF-UHFFFAOYSA-N 1-(dimethylamino)ethyl prop-2-enoate Chemical compound CN(C)C(C)OC(=O)C=C NFTVTXIQFYRSHF-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical group CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Chemical group 0.000 claims description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical group ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 2
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical group CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical group CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical group CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical group CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- AKAMNXFLKYKFOJ-UHFFFAOYSA-N 2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1F AKAMNXFLKYKFOJ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000009749 continuous casting Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 24
- 238000001914 filtration Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- DYDCPNMLZGFQTM-UHFFFAOYSA-N delafloxacin Chemical compound C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- DPBJAVGHACCNRL-UHFFFAOYSA-N 2-(dimethylamino)ethyl prop-2-enoate Chemical group CN(C)CCOC(=O)C=C DPBJAVGHACCNRL-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- KBESHLYCSZINAJ-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(Cl)=C1F KBESHLYCSZINAJ-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- VMEZXMFPKOMWHR-UHFFFAOYSA-N (dimethylamino)methyl prop-2-enoate Chemical compound CN(C)COC(=O)C=C VMEZXMFPKOMWHR-UHFFFAOYSA-N 0.000 description 1
- UJZDVMQPVOHSDG-UHFFFAOYSA-N 6-(dimethylamino)hexyl prop-2-enoate Chemical compound CN(C)CCCCCCOC(=O)C=C UJZDVMQPVOHSDG-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241001288468 Melita Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BEYVOSILLLPHNN-UHFFFAOYSA-N benzene;quinoline Chemical group C1=CC=CC=C1.N1=CC=CC2=CC=CC=C21 BEYVOSILLLPHNN-UHFFFAOYSA-N 0.000 description 1
- SVYAAXBYGFOKAF-UHFFFAOYSA-N butanoyl butanoate;2-methylpropanoyl 2-methylpropanoate Chemical compound CCCC(=O)OC(=O)CCC.CC(C)C(=O)OC(=O)C(C)C SVYAAXBYGFOKAF-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- VMXLACIKUJJQTC-UHFFFAOYSA-N ethyl 1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-[3-(2-methylpropanoyloxy)azetidin-1-yl]-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(N3CC(C3)OC(=O)C(C)C)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1=NC(N)=C(F)C=C1F VMXLACIKUJJQTC-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a new preparation method of delafloxacin meglumine, which adopts cheap 2,4, 5-trifluoro benzoic acid as a starting material, and the target product delafloxacin meglumine is obtained through 7 steps of reactions, and the total yield is as high as 85% -95%. In addition, the purity of the delafloxacin meglumine obtained by the method is more than 99%. The preparation method adopts multi-step continuous casting, has simple operation, low cost of required equipment and raw materials, convenient post-treatment of each step and higher purity of the intermediate.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of delafloxacin meglumine.
Background
Delafloxacin (delafloxacin) was developed by Wakunaga pharmaceutical company, and a new generation of broad-spectrum fluoroquinolone antibiotics developed by later-authorized melita pharmaceutical company. In 2017, delafloxacin (trade name Baxdela TM ) Are marketed for the treatment of acute bacterial skin and skin structure infections caused by susceptible bacteria. Compared with other fluoroquinolone antibacterial drugs, delafloxacin has more excellent activity against gram-positive bacteria.
The chemical formula of delafloxacin is: 1- (6-amino-3, 5-difluoropyridin-2-yl) -6-fluoro-7- [3- (isobutyryloxy) azetidin-1-yl ] -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester, having the structure:
WO9711068 discloses a process for the preparation of delafloxacin, the synthetic route of which is shown below:
the synthetic route is characterized in that the chlorine atom on the Yu Dela quinoline benzene ring is introduced by a substrate 3-chloro-2, 4, 5-trifluoro-benzoic acid. However, the cost of using 3-chloro-2, 4, 5-trifluorobenzoic acid as a reaction raw material is high. Furthermore, the patent does not disclose the meglumine salt of delafloxacin.
CN108084161a discloses a preparation method of delafloxacin meglumine, the synthetic route of which is shown as follows:
the synthetic route still uses 3-chloro-2, 4, 5-trifluoro-benzoic acid as a reaction raw material, and has high cost. Furthermore, the total yield of final product delafloxacin meglumine is only about 60%, which is low.
Therefore, there is a need to develop a new process for the preparation of delafloxacin meglumine at lower cost and with higher overall yields.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel preparation method of delafloxacin meglumine, which adopts cheap 2,4, 5-trifluoro-benzoic acid as a starting material, and obtains the target product delafloxacin meglumine through 7 steps of reactions, wherein the total yield is as high as 85% -95%.
In order to achieve the above object, the present invention provides the following technical solutions.
A process for the preparation of delafloxacin meglumine comprising:
step a: reacting reactant II with an acyl chloride reagent to form compound III;
step b: by reacting compound III with N, N-dimethylaminoacrylic acid C 1 -C 6 Alkyl ester reacts to generate a compound IV;
step c: reacting compound IV with 2, 6-diamino-3, 5-difluoropyridine to form compound V;
step d: the compound V is subjected to ring-closure reaction in the presence of alkali to obtain a compound VI;
step e: the acid addition salt of 3-hydroxy azetidine is subjected to substitution reaction with a compound VI, and the obtained substituted product is subjected to acylation reaction with an acylating agent, so that a compound VII is obtained;
step f: the compound VII and a chlorinating agent are subjected to chlorination reaction on a benzene ring, and the obtained product is subjected to hydrolysis reaction in the presence of alkali, so that the compound VIII is obtained; and
step g: reacting compound VIII with meglumine to form a salt to give delafloxacin meglumine of formula I:
wherein R may be C 1 -C 6 Alkyl or phenyl.
Preferably, the acid chloride reagent in step a may be thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride. In some embodiments, the acid chloride reagent in step a is thionyl chloride.
Preferably, the molar ratio of reactant II to the acid chloride reagent is 1 (1-2), preferably 1 (1.2-1.5). Specifically, the molar ratio of reactant II to the acid chloride reagent may be 1:2, 1:1.9, 1:1.8, 1:1.7, 1:1.6, 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1, or 1:1.
Preferably, the reaction of step a is carried out in an organic solvent selected from one or more of Dichloromethane (DCM), toluene, acetonitrile and N, N-Dimethylformamide (DMF). Specifically, the organic solvent may be a mixture of dichloromethane and N, N-dimethylformamide, a mixture of toluene and N, N-dimethylformamide, or a mixture of acetonitrile and N, N-Dimethylformamide (DMF). The reaction temperature in step a may be from 0 to 200 ℃, preferably from 0 to 100 ℃, more preferably from 5 to 80 ℃. The reaction time in step a may be from 1 to 48 hours, preferably from 1 to 24 hours. In some embodiments, step a comprises: mixing the compound II with an organic solvent, stirring and cooling, dropwise adding an acyl chloride reagent dissolved in the organic solvent, and heating and refluxing for reaction after the dropwise adding is finished.
Preferably, after the reaction of step a is completed, distillation under reduced pressure is performed. The temperature of the reduced pressure distillation may be 30 to 100 ℃, preferably 30 to 80 ℃.
Preferably, N, N-dimethylaminoacrylic acid C 1 -C 6 The alkyl ester may be N, N-dimethylaminomethyl acrylate, N-dimethylaminoethyl acrylate, N-dimethylaminopropyl acrylate, N-dimethylaminobutyl acrylate, N-dimethylaminopentyl acrylate or N, N-dimethylaminohexyl acrylate. In some embodiments, N, N-dimethylaminoacrylic acid C 1 -C 6 The alkyl ester is N, N-dimethylamino ethyl acrylate.
Preferably, compound III is reacted with N, N-dimethylaminoacrylic acid C 1 -C 6 Molar ratio of alkyl esters1 (1-1.5), preferably 1 (1-1.3). Specifically, compound III and N, N-dimethylaminoacrylic acid C 1 -C 6 The molar ratio of alkyl esters may be 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1, or 1:1. In some embodiments, the N, N-dimethylaminoacrylic acid C 1 -C 6 The alkyl ester is N, N-dimethylamino ethyl acrylate.
Preferably, the reaction of step b is carried out in an organic solvent selected from one or more of dichloromethane, toluene, acetonitrile, triethylamine (TEA), N-dimethylformamide and N, N-dimethylacetamide. Specifically, the organic solvent may be a mixture of any one or more of dichloromethane, toluene and acetonitrile with any one or more of Triethylamine (TEA), N-dimethylformamide and N, N-dimethylacetamide. For example, the organic solvent may be a mixture of dichloromethane and triethylamine, toluene and triethylamine, acetonitrile and triethylamine, or the like. The reaction temperature in step b may be from 0 to 200 ℃, preferably from 20 to 100 ℃, more preferably from 20 to 80 ℃. The reaction time in step b may be from 1 to 24 hours, preferably from 1 to 12 hours. In some embodiments, step b comprises: n, N-dimethylaminoacrylic acid C 1 -C 6 The alkyl ester is mixed with the organic solvent, the compound III dissolved in the organic solvent is dripped into the obtained mixture, and after the dripping is finished, the temperature is raised for reaction.
Preferably, after the reaction of step b is completed, distillation under reduced pressure is performed. The temperature of the reduced pressure distillation may be 30 to 100 ℃, preferably 30 to 80 ℃.
Preferably, the molar ratio of compound IV to 2, 6-diamino-3, 5-difluoropyridine is 1 (1-1.5), preferably 1 (1-1.2). Specifically, the molar ratio of compound IV to 2, 6-diamino-3, 5-difluoropyridine may be 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1, or 1:1.
Preferably, the reaction of step c is carried out in an organic solvent selected from one or more of acetonitrile, N-methylpyrrolidone (NMP), glacial acetic acid, anhydrous formic acid, tetrahydrofuran, ethyl acetate and ethanol. Specifically, the organic solvent may be a mixture of one or two of glacial acetic acid and anhydrous formic acid and one or more of acetonitrile, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate and ethanol. For example, the organic solvent may be a mixture of acetonitrile and glacial acetic acid, a mixture of N-methylpyrrolidone and glacial acetic acid, a mixture of tetrahydrofuran and glacial acetic acid, a mixture of ethyl acetate and glacial acetic acid, or a mixture of ethanol and glacial acetic acid. The reaction temperature in step c may be from 0 to 80℃and preferably from 15 to 60 ℃. The reaction time in step c may be from 5 to 24 hours. In some embodiments, step c comprises: mixing the compound IV with an organic solvent, dropwise adding 2, 6-diamino-3, 5-difluoropyridine dissolved in the organic solvent into the obtained mixture at the temperature of 0-20 ℃, and heating for reaction after the dropwise adding is finished.
Preferably, after the reaction of step c is completed, the resulting mixture is cooled, and water is added dropwise thereto, and after stirring and filtration, the resulting cake is mixed with ethanol, and after filtration, dried.
Preferably, the base in step d is selected from K 2 CO 3 、Na 2 CO 3 NaOH and NaHCO 3 One or more of the following.
Preferably, the reaction of step d is carried out in an organic solvent selected from one or more of N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, N-dimethylformamide and N, N-dimethylacetamide. The reaction temperature in step d may be from 0 to 100 ℃, preferably from 20 to 50 ℃; the reaction time may be 1 to 10 hours.
Preferably, after the reaction of step d is completed, the resulting mixture can be directly used for the next reaction without any post-treatment.
Preferably, the acid addition salt of 3-hydroxyazetidine may be 3-hydroxyazetidine hydrochloride, 3-hydroxyazetidine sulfate, 3-hydroxyazetidine nitrate, 3-hydroxyazetidine sulfonate, 3-hydroxyazetidine mesylate, or 3-hydroxyazetidine succinate. In some embodiments, the acid addition salt of 3-hydroxyazetidine is 3-hydroxyazetidine hydrochloride.
Preferably, the molar ratio of compound VI to the acid addition salt of 3-hydroxyazetidine is 1 (1-1.5), preferably 1 (1-1.2). Specifically, the molar ratio of compound VI to the acid addition salt of 3-hydroxyazetidine may be 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1, or 1:1.
Preferably, the substitution reaction in step e is carried out in an organic solvent selected from one or more of N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, N-dimethylformamide and N, N-dimethylacetamide. The substitution reaction in step e may be carried out in the presence of a base selected from K 2 CO 3 、Na 2 CO 3 NaOH and NaHCO 3 One or more of the following. The temperature of the substitution reaction may be 20-100 ℃, preferably 50-100 ℃. The time for the substitution reaction may be 1 to 5 hours.
Preferably, after completion of the substitution reaction in step e and before the acylation reaction, the reaction mixture is filtered while hot to obtain a filtrate.
Preferably, the acylating reagent in step e may be acetic anhydride, propionic anhydride, isopropyl anhydride, butyric anhydride isobutyric anhydride, pivalic anhydride, hexanoic anhydride, benzoic anhydride, acetyl chloride or benzoyl chloride. In some embodiments, the acylating reagent is acetic anhydride. The molar ratio of substitution product to acylating agent may be 1 (1-3), preferably 1 (1-2.5). Specifically, the molar ratio of substitution product to acylating agent may be 1:3, 1:2.9, 1:2.8, 1:2.7, 1:2.6, 1:2.5, 1:2.4, 1:2.3, 1:2.2, 1:2.1, 1:2, 1:1.9, 1:1.8, 1:1.7, 1:1.6, 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1, or 1:1. The temperature of the acylation reaction may be 20-50 ℃, preferably 20-30 ℃; the reaction time may be 0.5 to 3 hours.
Preferably, after the acylation reaction is completed, an acid (e.g., citric acid or hydrochloric acid) is added dropwise to the resultant mixture, and after filtration, the resultant cake is mixed with toluene and ethanol, filtered again, and dried.
Preferably, the chlorinating agent in step f may be N-chlorosuccinimide (NCS). Preferably, the molar ratio of compound VII to chlorinating agent is 1 (1-1.5), preferably 1 (1-1.2). Specifically, the molar ratio of compound VII to chlorinating agent may be 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1 or 1:1.
Preferably, the chlorination in step f is carried out in an organic solvent, which may be ethyl acetate, ethanol, acetonitrile, chloroform, tetrahydrofuran, carbon tetrachloride, dichloromethane, DMF or DME. In some embodiments, the organic solvent is ethyl acetate. The chlorination reaction is carried out under strong acid conditions, for example in the presence of concentrated sulfuric acid. The temperature of the chlorination reaction can be 0-20 ℃; the reaction time may be 2 to 6 hours.
Preferably, after the chlorination reaction is completed, quenching and liquid separation are performed, and the resulting organic phase is concentrated.
Preferably, the base in step f may be selected from K 2 CO 3 、Na 2 CO 3 NaOH and NaHCO 3 One or more of the following. In some embodiments, the base in step f is NaHCO 3 . The temperature of the hydrolysis reaction can be 30-60 ℃; the reaction time may be 2 to 6 hours.
Preferably, after the hydrolysis reaction is completed, the resulting reaction mixture is filtered, preferably while hot; and acid (e.g., citric acid or hydrochloric acid) is added dropwise to the obtained filtrate, and the filtrate is filtered again and dried. Preferably, the temperature is reduced prior to filtration.
Preferably, the molar ratio of compound VIII to meglumine is 1 (1-1.5), preferably 1 (1-1.2). Specifically, the molar ratio of compound VIII to meglumine may be 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1 or 1:1.
Preferably, the reaction of step g is carried out in a solvent which may be selected from one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and water. Specifically, the solvent may be a mixture of water and any one or more of methanol, ethanol, isopropanol, acetone, acetonitrile and tetrahydrofuran. For example, the solvent may be a mixture of methanol and water, ethanol and water, isopropanol and water, acetone and water, acetonitrile and water, or tetrahydrofuran and water. The reaction temperature in step g may be 30-70 ℃; the reaction time may be 1 to 5 hours. In some embodiments, compound VIII is mixed with a solvent, warmed, and meglumine dissolved in the solvent is added dropwise to the reaction mixture, and the reaction is incubated.
Preferably, after the reaction of step g is completed, cooling, filtering and drying are performed.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention provides a new preparation method of delafloxacin meglumine, which adopts cheap 2,4, 5-trifluoro benzoic acid as a starting material, and the target product delafloxacin meglumine is obtained through 7 steps of reactions, wherein the total yield is as high as 85% -95%. In addition, the purity of the delafloxacin meglumine obtained by the method is more than 99%.
2. The preparation method adopts multi-step continuous casting, has simple operation, low cost of required raw materials and equipment, convenient post-treatment of each step and higher purity of the intermediate.
Detailed Description
In order to make the contents of the present invention more easily understood, the technical scheme of the present invention will be further described with reference to the specific embodiments, but the present invention is not limited thereto. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention. Unless otherwise indicated, the raw materials and reagents used in the examples were all commercially available. The reagents, instruments or procedures not described herein are those routinely determinable by one of ordinary skill in the art.
Example 1: synthesis of Compound III
To a 100mL single vial was added compound II (5.00 g,28.39 mmol), DCM (15 mL) and DMF (0.15 mL), and a solution of thionyl chloride (5.07 g,42.59 mmol) in DCM (10 mL) was slowly added dropwise with stirring and cooling to 5 ℃. After the dripping is finished, the temperature is raised to 40 ℃ for reflux reaction for 10 hours, and the mixture is distilled under reduced pressure at 30-40 ℃ until no fraction flows out, so that light yellow oily matter is obtained and is directly used for the next step.
Example 2: synthesis of Compound III
To a 250mL single-necked flask, a solution of Compound II (20.00 g,113.58 mmol), toluene (100 mL) and DMF (0.6 mL) was added dropwise with stirring to reduce the temperature to 5℃and a solution of thionyl chloride (20.27 g,170.37 mmol) in toluene (40 mL) was slowly added dropwise. After the dripping is finished, the temperature is raised to 80 ℃ for reaction for 3 hours, and the mixture is distilled under reduced pressure at 40-80 ℃ until no fraction flows out, so that yellow oily matter is obtained and is directly used for the next step.
Example 3: synthesis of Compound IV
To a 100mL single-port flask was added N, N-dimethylaminoethyl acrylate (4.06 g,28.39 mmol), TEA (3.16 g,31.23 mmol) and DCM (15 mL), and a solution of the whole oil (28.39 mmol) prepared in example 1 in DCM (10 mL) was added dropwise at room temperature. After the dripping is finished, the temperature is raised to 50 ℃ for violent reflux reaction for 6 hours, and the mixture is distilled under reduced pressure at 30-40 ℃ until no fraction flows out, so that a reddish brown oily substance is obtained and is directly used for the next step.
Example 4: synthesis of Compound IV
To a 250mL single-necked flask were added N, N-dimethylaminoethyl acrylate (16.26 g,113.58 mmol), TEA (12.64 gg,124.94 mmol) and toluene (60 mL), and a toluene (40 mL) solution of the total oil (113.58 mmol) prepared in example 2 was added dropwise at room temperature; after the dripping is finished, the temperature is raised to 50 ℃ for reaction for 6 hours, and the mixture is distilled under reduced pressure at 40-60 ℃ until no fraction flows out, so that a reddish brown oily matter is obtained and is directly used for the next step.
Example 5: synthesis of Compound V
All of the oil (28.39 mmol) from example 3 was mixed with acetonitrile (25 mL) and glacial acetic acid (2.69 g,44.72 mmol) and a solution of 2, 6-diamino-3, 5-difluoropyridine (4.32 g,29.77 mmol) in acetonitrile (25 mL) was added dropwise at 15 ℃. After the completion of the dropwise addition, the temperature was raised to 55℃and the reaction was carried out for 16.0 hours. Cooling to 20 ℃, dropwise adding water (50 mL), stirring for 30min, filtering, pulping a filter cake with 95% ethanol (30 mL) at room temperature for 1h, suction filtering, and vacuum drying the filter cake at 60 ℃ for 12h to obtain 10.85g of bright yellow solid with purity of 99.23% and yield of 95.2% (namely, the total yield of three steps of examples 1, 3 and 5).
Example 6: synthesis of Compound V
All of the oil (113.58 mmol) from example 4 was mixed with NMP (100 mL) and glacial acetic acid (10.23 g,170.36 mmol) and a solution of 2, 6-diamino-3, 5-difluoropyridine (17.30 g,119.22 mmol) in NMP (100 mL) was added dropwise at 15 ℃. After the completion of the dropwise addition, the temperature was raised to 55℃and the reaction was carried out for 16.0 hours. Cooling to 20 ℃, dropwise adding water (200 mL), stirring for 30min, filtering, pulping a filter cake with 95% ethanol (100 mL) at room temperature for 1h, suction filtering, and vacuum drying the filter cake at 60 ℃ for 12h to obtain 44.30g of bright yellow solid with purity of 99.52% and yield of 97.2% (namely, the total yield of three steps of examples 2,4 and 6).
Example 7: synthesis of Compound VI
To a 500mL single-necked flask, compound V (20.00 g,49.84 mmol), potassium carbonate (20.67 g,149.52 mmol) and NMP (140 mL) were added at room temperature, and the mixture was stirred at 35℃for 4 hours to obtain a reaction solution of Compound VI, which was directly used in the next reaction.
Example 8: synthesis of Compound VII
To the whole reaction solution of compound VI (49.84 mmol) obtained in example 7 was added 3-hydroxyazetidine hydrochloride (5.46 g,49.84 mmol) with stirring, heating to 70 ℃ and stirring for 2 hours, filtering, adding acetic anhydride (11.20 g,109.71 mmol) to the filtrate, reacting at 25 ℃ for 1 hour, then slowly dropwise adding 10% citric acid (80.00 g), stirring for 0.5 hours, followed by filtering, washing the cake with water (15.00 g) twice, mixing the cake with 50% toluene+50% ethanol solution (80 mL), stirring for 2 hours at 70 ℃, cooling to room temperature and suction filtering, vacuum drying the cake at 60 ℃ for 8 hours to obtain 23.20g of off-white solid with purity of 99.41% yield 97.7% (i.e., total yield of both steps of examples 7 and 8).
Example 9: synthesis of Compound VIII
To a 250mL single-necked flask, a mixed solution of Compound VII (20.00 g,42.00 mmol) and ethyl acetate (60 mL), NCS (5.61 g,42.00 mmol), ethyl acetate (100 mL) and concentrated sulfuric acid (0.13 g,1.33 mmol) was added dropwise at 10℃and after the completion of the addition, the reaction was allowed to stand at 15℃for 4 hours. Thereafter, 3% sodium hydrogencarbonate solution (40.00 g) was added dropwise to quench, the solution was separated, and the organic phase was washed with 10% sodium sulfite (44.00 g) and concentrated to dryness at 40℃to give a concentrated organic matter.
The organics were concentrated by stirring with ethanol (100 mL) and 10% NaOH solution (80.00 g) was added. Then, the temperature was raised to 50℃and the reaction was carried out for 4 hours. After that, filtration was carried out, and 10% glacial acetic acid (108.00 g) was slowly added dropwise to the filtrate, and after the completion of the dropwise addition, the mixture was stirred at a constant temperature for 1 hour. After cooling to room temperature, the mixture was filtered, the filter cake was washed twice (40 mL), and dried under vacuum at 60℃for 16h to give 17.70g of a yellow solid, purity 99.22%, yield 95.6%.
1H NMR((400MHz,DMSO)δ14.63(brs,1H),8.38(d,J=8.2Hz,1H),7.93(d,J=13.8Hz,1H),7.81(dd,1H),6.75(s,2H),5.69(d,1H),4.61(dt,2H),4.45(m,1H),4.23(dt,2H)。
Example 10: synthesis of Compound I
To a 250mL single-necked flask, a mixed solution of Compound VIII (15.00 g,34.03 mmol) and isopropyl alcohol (90 mL), warmed to 50℃and meglumine (7.00 g,35.86 mmol) and water (30 mL) was added dropwise thereto, and the reaction was continued for 3 hours. After cooling to 10 ℃, filtering, and vacuum drying the filter cake for 16 hours at 50 ℃ to obtain 22.30g of white solid with the purity of 99.6 percent and the yield of 98.7 percent.
1H NMR(400MHz,DMSO)δ8.37(d,1H),7.90(t,J=8.2Hz,1H),7.77(d,J=13.8Hz,1H),6.67(s,2H),5.71(s,1H),4.65(s,1H),4.45(m,1H),4.12-3.71(m,4H),3.64-3.58(m,6H),3.47(s,3H),3.44-3.25(m,2H)。
The present invention is not limited to the above-mentioned embodiments, and any changes or substitutions that can be easily understood by those skilled in the art within the technical scope of the present invention are intended to be included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A process for the preparation of delafloxacin meglumine comprising:
step a: reacting reactant II with an acyl chloride reagent to form compound III;
step b: by reacting compound III with N, N-dimethylaminoacrylic acid C 1 -C 6 Alkyl ester reacts to generate a compound IV;
step c: reacting compound IV with 2, 6-diamino-3, 5-difluoropyridine to form compound V;
step d: the compound V is subjected to ring-closure reaction in the presence of alkali to obtain a compound VI;
step e: the acid addition salt of 3-hydroxy azetidine is subjected to substitution reaction with a compound VI, and the obtained substituted product is subjected to acylation reaction with an acylating agent, so that a compound VII is obtained;
step f: the compound VII and a chlorinating agent are subjected to chlorination reaction on a benzene ring, and the obtained product is subjected to hydrolysis reaction in the presence of alkali, so that the compound VIII is obtained; and
step g: reacting compound VIII with meglumine to form a salt to give delafloxacin meglumine of formula I:
wherein R may be C 1 -C 6 Alkyl or phenyl.
2. The method according to claim 1, wherein the acid chloride reagent in step a is thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride;
the mol ratio of the reactant II to the acyl chloride reagent is 1 (1-2);
the reaction of step a is carried out in an organic solvent selected from one or more of dichloromethane, toluene, acetonitrile and N, N-dimethylformamide;
the reaction temperature in step a is preferably from 0 to 200 ℃.
3. The process according to claim 1 or 2, wherein the acylating agent in step e is acetic anhydride, propionic anhydride, isopropyl anhydride, butyric anhydride, isobutyric anhydride, pivalic anhydride, hexanoic anhydride, benzoic anhydride, acetyl chloride or benzoyl chloride;
the molar ratio of the substituted product to the acylating agent is 1 (1-3);
the temperature of the acylation reaction is 20-50 ℃.
4. The process according to claim 1 or 2, wherein the chlorinating agent in step f is N-chlorosuccinimide;
the mol ratio of the compound VII to the chlorinating agent is 1 (1-1.5);
the chlorination reaction in the step f is carried out in an organic solvent, wherein the organic solvent is ethyl acetate, ethanol, acetonitrile, chloroform, tetrahydrofuran, carbon tetrachloride, dichloromethane, DMF or DME;
the chlorination reaction is carried out under the condition of strong acid;
the temperature of the chlorination reaction is 0-20 ℃.
5. The process according to claim 1 or 2, wherein in step b, N-dimethylaminoacrylic acid C 1 -C 6 The alkyl ester is N, N-dimethylamino methyl acrylate, N-dimethylamino ethyl acrylate, N-dimethylamino propyl acrylate, N-dimethylamino butyl acrylate, N-dimethylamino amyl acrylate or N, N-dimethylamino hexyl acrylate;
compound III and N, N-dimethylaminoacrylic acid C 1 -C 6 The molar ratio of the alkyl ester is 1 (1-1.5);
the reaction of step b is carried out in an organic solvent selected from one or more of dichloromethane, toluene, acetonitrile, triethylamine, N-dimethylformamide and N, N-dimethylacetamide;
the reaction temperature in step b is 0-200 ℃.
6. The process according to claim 1 or 2, wherein in step c, the molar ratio of compound IV to 2, 6-diamino-3, 5-difluoropyridine is 1 (1-1.5);
the reaction of step c is carried out in an organic solvent selected from one or more of acetonitrile, N-methylpyrrolidone, glacial acetic acid, anhydrous formic acid, tetrahydrofuran, ethyl acetate and ethanol;
the reaction temperature in step c is 0-80 ℃.
7. The process according to claim 1 or 2, wherein the base in step d is selected from K 2 CO 3 、Na 2 CO 3 NaOH and NaHCO 3 One or more of the following;
the reaction of step d is carried out in an organic solvent selected from one or more of N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, N-dimethylformamide and N, N-dimethylacetamide;
the reaction temperature in step d is 0-100 ℃.
8. The process according to claim 1 or 2, wherein the acid addition salt of 3-hydroxyazetidine in step e is 3-hydroxyazetidine hydrochloride, 3-hydroxyazetidine sulfate, 3-hydroxyazetidine nitrate, 3-hydroxyazetidine sulfonate, 3-hydroxyazetidine mesylate or 3-hydroxyazetidine succinate;
the molar ratio of compound VI to the acid addition salt of 3-hydroxyazetidine is 1 (1-1.5);
the substitution reaction in the step e is carried out in an organic solvent, wherein the organic solvent is selected from one or more of N-methyl pyrrolidone, dimethyl sulfoxide, acetonitrile, N-dimethylformamide and N, N-dimethylacetamide;
the temperature of the substitution reaction may be 20-100 ℃.
9. The process according to claim 1 or 2, wherein the base in step f is selected from K 2 CO 3 、Na 2 CO 3 NaOH and NaHCO 3 One or more of the following;
the temperature of the hydrolysis reaction is 30-60 ℃.
10. The process according to claim 1 or 2, wherein the molar ratio of compound VIII to meglumine is 1 (1-1.5), preferably 1 (1-1.2);
the reaction of step g is carried out in a solvent selected from one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and water;
the reaction temperature in step g is 30-70 ℃.
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