CN117659009A - Preparation method of moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane - Google Patents
Preparation method of moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane Download PDFInfo
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- CN117659009A CN117659009A CN202311642514.2A CN202311642514A CN117659009A CN 117659009 A CN117659009 A CN 117659009A CN 202311642514 A CN202311642514 A CN 202311642514A CN 117659009 A CN117659009 A CN 117659009A
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- China
- Prior art keywords
- ethylene glycol
- product
- solvent
- reaction
- diazabicyclo
- Prior art date
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- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical group COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 title claims abstract description 26
- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4as,7as)-2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 17
- 230000009467 reduction Effects 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 12
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims abstract description 8
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 35
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 25
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 13
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 12
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 12
- 150000001336 alkenes Chemical class 0.000 claims description 12
- 125000004989 dicarbonyl group Chemical group 0.000 claims description 12
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 12
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 238000007142 ring opening reaction Methods 0.000 claims description 5
- 229910018072 Al 2 O 3 Inorganic materials 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 229910018879 Pt—Pd Inorganic materials 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- YHBDIEWMOMLKOO-UHFFFAOYSA-I pentachloroniobium Chemical compound Cl[Nb](Cl)(Cl)(Cl)Cl YHBDIEWMOMLKOO-UHFFFAOYSA-I 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 230000006698 induction Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000007791 liquid phase Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 description 3
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 description 3
- AFYZAHZKOFBVLE-UONOGXRCSA-N (4as,7as)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine Chemical compound C([C@H]1NCCC[C@H]1C1)N1CC1=CC=CC=C1 AFYZAHZKOFBVLE-UONOGXRCSA-N 0.000 description 2
- AFYZAHZKOFBVLE-UHFFFAOYSA-N 6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine Chemical compound C1C2CCCNC2CN1CC1=CC=CC=C1 AFYZAHZKOFBVLE-UHFFFAOYSA-N 0.000 description 2
- DIHIVGQFGZLZPN-UHFFFAOYSA-N 6-benzyl-2,3,4,4a,5,7a-hexahydro-1H-pyrrolo[3,4-b]pyridin-7-one Chemical compound C(C1=CC=CC=C1)N1C(C2NCCCC2C1)=O DIHIVGQFGZLZPN-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011012 grey crystal Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RRBLNPCNHNHAFW-NEPJUHHUSA-N (4ar,7as)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C([C@H]1NCCC[C@H]1C1=O)N1CC1=CC=CC=C1 RRBLNPCNHNHAFW-NEPJUHHUSA-N 0.000 description 1
- DWUBVULEMQOCPO-UHFFFAOYSA-N 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C1C2=NC=CC=C2C(=O)N1CC1=CC=CC=C1 DWUBVULEMQOCPO-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241000588655 Moraxella catarrhalis Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229910002845 Pt–Ni Inorganic materials 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229940062316 avelox Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XPAOPAPDCRLMTR-UHFFFAOYSA-N ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxoquinoline-3-carboxylate Chemical compound C12=C(OC)C(F)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 XPAOPAPDCRLMTR-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000012808 vapor phase Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a preparation method of a moxifloxacin side chain ((S, S) -2, 8-diazabicyclo [4,3,0] nonane), and belongs to the field of medicines. The invention takes 2, 3-pyridine diformate and R-alpha-phenethylamine as raw materials, and obtains a high chiral key intermediate through cyclization, hydrogenation, oxidation and rehydrogenation, and finally obtains a target product moxifloxacin side chain through reduction and deprotection. Compared with the traditional synthesis route, the chiral key intermediate is directly obtained through chiral induction, so that the resolution after the synthesis of the raceme is avoided, and the atomic economy is met. And the reaction yield is improved on the basis of ensuring high stereoselectivity of the product by optimizing the process. Meanwhile, the reaction is mild, the operation is simple, the requirements of green chemistry are met, and the industrial large-scale production is facilitated.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane.
Background
The moxifloxacin hydrochloride tablet raw grinding product AVELOX is developed by germany bayer company. The moxifloxacin hydrochloride is mainly used for treating infections caused by sensitive bacteria of adults (more than or equal to 18 years old), including acute bacterial sinusitis, acute attacks of chronic bronchitis, community-acquired pneumonia, complicated skin and skin tissue infections, complicated intraperitoneal infections and the like, and is a medical insurance class B product in the catalogue of national basic medical insurance, industrial injury insurance and fertility insurance medicines.
Moxifloxacin hydrochloride is a fourth-generation novel quinolone antibacterial agent, has smaller adverse reaction compared with the prior third-generation drug, and shows stronger antibacterial activity on partial infection, such as main pathogenic bacteria of respiratory tract infection, such as streptococcus pneumoniae, haemophilus influenzae, moraxella catarrhalis, klebsiella pneumoniae and the like; meanwhile, the preparation method has the advantages of wide antibacterial spectrum, difficult generation of drug resistance, effectiveness on common drug-resistant bacteria, long half-life and the like.
The moxifloxacin is formed by connecting a moxifloxacin side chain ((S, S) -2, 8-diazabicyclo [4,3,0] nonane) with gative ester (1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ethyl ester). For the synthesis of a key chiral intermediate moxifloxacin side chain, two methods are mainly available, namely (1) chemical resolution; (2) asymmetric hydrogenation of noble metal chiral ligands. Patent CN201310138812.8 discloses a method for industrially producing moxifloxacin side chains, which comprises the steps of A, dissolving 3-aldehyde pyridine-2-carboxylic acid and benzylamine in a mixed solvent of distilled water and an organic solvent, and putting the mixed solvent into a high-pressure reaction kettle for catalytic hydrogenation to obtain 6-benzyl-hexahydropyrrolo [3,4-b ] pyridin-7-one; B. dissolving 6-benzyl-hexahydropyrrolo [3,4-b ] pyridine-7-one in an organic solvent, adding a reducing agent, and carrying out reduction reaction to obtain 6-benzyl-octahydro-pyrrolo [3,4-b ] pyridine; C. dissolving 6-benzyl-octahydro-pyrrolo [3,4-b ] pyridine in an organic solvent, and adding D- (-) -tartaric acid for resolution to obtain (s, s) -6-benzyl-octahydropyrrolo [3,4-b ] pyridine; D. dissolving (S, S) -6-benzyl-octahydropyrrolo [3,4-b ] pyridine in an organic solvent, and putting the organic solvent into a high-pressure reaction kettle for catalytic hydrogenation to remove benzyl to obtain (S, S) -2, 8-diazabicyclo [4.3.0] nonane. The scheme of the invention has high production efficiency, but chemical resolution is not friendly to atom economy, and the intermediate with another configuration cannot be completely recovered. Patent CN201810418400.2 discloses a preparation method of an iridium-catalyzed moxifloxacin side chain intermediate and patent CN201810418391.7 discloses a preparation method of a rhodium-catalyzed moxifloxacin side chain intermediate, which comprises the following steps: under the catalysis of chiral catalyst, the asymmetric hydrogenation reaction of 6-benzyl-pyrrolo [3,4-b ] pyridine-5, 7-dione and hydrogen in organic solvent is carried out to obtain the (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane. The preparation method has the advantages of high efficiency, strong universality on substrates and high enantioselectivity, but the asymmetric hydrogenation is carried out by using heavy metal iridium or rhodium and chiral ligands, so that the production cost is too high, and the industrial production is not facilitated. Improvements in the process for preparing them are urgently needed.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane, which realizes high selectivity, high yield, low cost and green preparation and is convenient for industrial production and application.
In order to achieve the aim of the invention, the chiral key intermediate is directly obtained through chiral induction, and resolution after synthesis of a raceme is avoided. .
The method is realized by the following technical scheme:
the following synthetic route is adopted:
the method comprises the following steps:
(1) Mixing the pyridine 2, 3-dicarboxylic acid SM1 and acetic anhydride, and performing cyclization reaction to obtain a ring-closing product I, wherein purification is not needed, and the next step is directly performed;
(2) Adding a solvent into a ring-closing product I, R-alpha-phenethylamine SM2, adding acetic anhydride after ring opening reaction to obtain a ring-closing product II, and directly carrying out the next step without purification;
(3) Under the condition of hydrogen, mixing the ring-closing product II, a solvent and a metal catalyst for hydrogenation reaction to obtain a pyridine ring reduced product III, and directly carrying out the next step without purification;
(4) Mixing the pyridine ring reduced product III, an oxidant and a solvent to perform selective double bond oxidation reaction to obtain an olefin conjugated dicarbonyl product IV, and recrystallizing and purifying;
(5) Under the condition of hydrogen, mixing the olefin conjugated dicarbonyl product IV, a solvent and a metal catalyst for hydrogenation reaction to obtain a key chiral product V, and recrystallizing and purifying;
(6) Mixing the key chiral product V, a reducing agent, lewis acid and a solvent for a reduction carbonyl reaction to obtain a carbonyl reduction product VI;
(7) And under the condition of hydrogen, mixing the carbonyl reduction product VI, a solvent and a metal catalyst for deprotection to obtain the moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane VII.
The reaction temperature in the step (1) is 80-125 ℃ and the reaction time is 1-3 h.
The feeding sequence in the step (2) is as follows: and adding a solvent into the ring-closing product I to dissolve the ring-closing product I, cooling, slowly dropwise adding R-alpha-phenethylamine SM2, and controlling the temperature. After the dripping is finished, heating and preserving heat for reaction. After the ring opening reaction, the solvent is evaporated, and acetic anhydride is added to complete the ring closing reaction. The temperature reduction control is as follows: -10 ℃, and the temperature of the dripping is controlled as follows: the temperature is between 10 ℃ below zero and 10 ℃, and the heat preservation reaction is controlled to be between 30 and 50 ℃.
The solvent in the step (2) is at least one or more than two of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetone, butanone and acetonitrile.
The solvent in the step (3) is ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether,At least one or more of ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetone, butanone and acetonitrile. The metal catalyst in the step (3) is Pd/C, pd/Al 2 O 3 Or Pd (OH) 2 /C。
In the step (4), the oxidant is manganese dioxide or/and hydrogen peroxide.
In the step (4), the selected solvent is at least one or more than two of tetrahydrofuran, dichloromethane, chloroform, toluene, xylene and acetonitrile; the recrystallization solvent is at least one or more of methanol, ethanol, dimethyl sulfoxide, dichloromethane, ethyl acetate, butyl acetate, tetrahydrofuran, cyclohexane and N-methylpyrrolidone.
The solvent in the step (5) is at least one or more than two of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetone, butanone and acetonitrile. The metal catalyst in the step (5) is Pd/C, pd/Al 2 O 3 Or Pd (OH) 2 /C。
The reducing agent in the step (6) is one of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and potassium borohydride.
The Lewis acid in the step (6) is at least one or more than two of aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride.
The solvent in the step (6) is at least one or more than two of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetone, butanone and acetonitrile.
The solvent in the step (7) is at least one or more than two of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, petroleum ether, diethyl ether, acetone, butanone and acetonitrile.
The metal catalyst in the step (7) is one of Pt-Pd/C, pt-Ni/C, pd-Ni/C.
The reaction condition of the step (7) is 80-120 ℃ for 8-15 h.
Compared with the prior art, the invention has the following positive and beneficial effects:
(1) Chiral key intermediates are directly obtained through chiral induction, so that resolution after synthesis of racemes is avoided, waste of subsequent materials is avoided, production cost is saved, environmental pollution is reduced, and atomic economy is met. Experiments show that chiral carbon on the bridge of a ring-closing product II obtained by the reaction of the ring-closing product I, R-alpha-phenethylamine SM2 and acetic anhydride is racemized, and then the chiral carbon on the bridge of a product III is racemized after pyridine ring reduction. In order to prepare a key chiral product V, R-alpha-phenethylamine SM2 is selected as an inducer, and in the reaction of preparing an olefin conjugated dicarbonyl product IV, a product III after pyridine ring reduction is subjected to selective double bond oxidation reaction through a conjugated induction effect; in the reaction for preparing the key chiral product V, the olefin conjugated dicarbonyl product IV is subjected to hydrogenation reaction through attribute induction effect, so that the key chiral product V is obtained.
(2) By optimizing the process, the reaction yield is improved on the basis of ensuring high stereoselectivity of the product. The reaction is mild, the operation is simple, the requirements of green chemistry are met, and the industrial large-scale production is facilitated. The intermediate related by the synthetic route can be directly used for the next step or recrystallization purification without column chromatography; and the catalytic hydrogenation and hydrogenation reduction steps are involved, and severe reaction conditions, expensive reagents and heavy polluted materials are not needed.
Drawings
FIG. 1 is a graph showing the results of liquid phase detection of the product prepared in step (2) of example 1;
FIG. 2 is a graph showing the results of liquid phase detection of the product prepared in step (3) of example 1;
FIG. 3 is a graph showing the results of liquid phase detection of the product prepared in step (4) of example 1;
FIG. 4 is a graph showing the results of liquid phase detection of the product prepared in step (5) of example 1;
FIG. 5 is a graph showing the chiral detection result of the product prepared in step (5) of example 1;
FIG. 6 is a graph showing the results of liquid phase detection of the product prepared in step (6) of example 1;
FIG. 7 is a graph showing the results of vapor phase detection of the product prepared in step (7) of example 1;
FIG. 8 is a graph showing the chiral detection result of the product prepared in step (7) of example 1;
FIG. 9 is a graph showing the nuclear magnetic resonance detection result of moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane prepared in example 1.
Detailed Description
The present invention will be described in more detail by way of examples, which should not be construed as limiting the scope of the invention.
Example 1
(1) In a 2L reaction flask, 500ml (1 v/m) of acetic anhydride was added to the compound 2, 3-pyridine diformate (500.02 g,2.99 mol), and the mixture was reacted at 110℃for 2.5 hours. Cooling to 80 deg.c and evaporating the solvent. Adding 500ml (1 v/m) methylene dichloride into the evaporated matter, stirring for 30min at 40-45 ℃, cooling, evaporating the solvent, and repeating the steps again to obtain a ring-closing product I. The next step is directly carried out without purification;
(2) 1500ml (3 v/m) of methylene dichloride is added into the evaporated matter, the temperature is reduced to 0-5 ℃, R-alpha-phenethylamine (398.68 g,3.29 mol) is slowly added dropwise, and the temperature is controlled between 0-10 ℃. After the dripping is finished, the temperature is raised to 45 ℃, and the temperature is kept for 1h. Cooling, evaporating the solvent, and completing the ring-opening reaction.
500ml (1 v/m) acetic anhydride was added to the evaporated material, and the mixture was reacted at 110℃for 3 hours, cooled to 80℃and the solvent was distilled off. 1000ml (2 v/m) of absolute ethyl alcohol is added into the evaporated-to-dryness matter, the temperature is reduced to 0-5 ℃, and the mixture is stirred for 1h. Suction filtration, rinsing the filter cake with absolute ethanol (200 ml x 3) to obtain grey crystal solid particles. Drying at 65deg.C with electrothermal air drying oven to obtain ring-closed product II 618.90g with yield of 90.11% and liquid phase purity of 99.64%, and the result is shown in figure 1.
(3) The ring-closed product II (502.05 g,1.99 mol) was dissolved in 3000mL of tetrahydrofuran, transferred to an autoclave, weighed and 5% wt Pd/C (26.01 g,5% wt) was added, the hydrogenation reactor pressure was set at 3MPa, the stirring speed was 300r/min, and the autoclave pressure was allowed to reach 3MPa, the temperature was set at 100℃and the hydrogenation reaction was carried out for 3 hours.
After the reaction is finished, the heating is closed, when the temperature in the kettle is lower than 40 ℃, the gas valve is slowly opened to release pressure to normal pressure, the kettle body is opened, the reaction liquid is taken out, a proper amount of diatomite is added for filtering, a filter cake is washed by 5V tetrahydrofuran, the filtrates are combined and concentrated to obtain a pyridine ring reduced product III 504.41g, the yield is 98%, the liquid phase purity is 97.90%, and the result is shown in figure 2.
(4) The pyridine ring reduced product III (425 g,1.65 mol) was weighed into a 5L reactor, 3L of methylene chloride was added for clearing, and then activated manganese dioxide (710 g,8.22 mol) was added in portions, and the mixture was stirred at 25℃for 12 hours. TLC control raw materials are reacted completely, the reaction is finished, the reaction solution is filtered by diatomite, the filtrate is concentrated to obtain a crude product, methylene dichloride/ethanol is recrystallized and purified to obtain 358.57g of olefin conjugated dicarbonyl product IV, the yield is 85.03 percent, the liquid phase purity is 98.19 percent, and the result is shown in figure 3.
(5) Weighing an olefin conjugated dicarbonyl product IV (336.9 g,1.31 mol), placing the olefin conjugated dicarbonyl product IV in a 10L reaction kettle, adding ethyl acetate 4L solution, weighing and adding 5%wt Pd/C (18.01 g, 5%wt), replacing a hydrogen balloon for three times, carrying out reflux hydrogenation at 70 ℃ for 24 hours, controlling the raw materials in TLC to react completely, filtering the reaction liquid by kieselguhr after the reaction is finished, concentrating the filtrate, adding 1.6L ethanol, stirring at room temperature for 0.5 hours, maintaining the temperature at not more than 30 ℃ for dropwise adding 117 mL of hydrochloric acid, cooling to 0-5 ℃ for stirring for 1-2 hours, filtering a filter cake, leaching the filter cake by using 35mL of ethanol, adding the obtained filter cake into dichloromethane, adding saturated sodium bicarbonate to adjust the pH value to 8-9, separating the liquid, concentrating the organic phase to dryness, and obtaining a key chiral product V288.63 g, wherein the yield is 85.6%, the liquid phase purity is 99.50%, and the chiral purity is 99.19% as shown in a graph of FIG. 4 and 5.
(6) Adding 630mL of ethylene glycol dimethyl ether into a 5L reaction kettle, stirring and cooling to 0-10 ℃, weighing aluminum chloride (84.93 g,0.64 mol) and controlling the temperature not to exceed 10 ℃ and adding the mixture into the kettle in batches, and weighing NaBH 4 (55.61 g,1.47 mol) was added to the kettle at a controlled temperature of not more than 10 ℃. The ring-closing product V (126.20 g,0.49 mol) was dissolved in ethylene glycol dimethylEther 250mL was added dropwise to the reaction solution. After the dripping is finished, the temperature is raised to 85 ℃ and the mixture is refluxed for 5 hours. TLC control, complete reaction of raw materials and end of reaction. Evaporating the glycol dimethyl ether under reduced pressure, adding 500mL of toluene, stirring uniformly, and cooling to 0-10 ℃. 189mL of concentrated hydrochloric acid is measured to 380mL of water, the mixture is shaken uniformly, and the mixture is dropwise added into the toluene solution at the temperature of not more than 10 ℃. After the addition, stirring for 2 hours at room temperature, heating to 90 ℃ for continuous stirring for 1-2 hours until the mixture is clarified, then continuously stirring for 2 hours, cooling to-5 ℃, adjusting the pH to 14 by using 50% NaOH solution, extracting by using toluene (250 mL 4), combining toluene layers, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain 109.15g of carbonyl reduction product VI, wherein the yield is 97%, the liquid phase purity is 96.16%, and the result is shown in figure 6.
(7) Carbonyl reduction product VI (100.00 g,0.43 mol) was dissolved in 2000mL of methanol, transferred to a 5L autoclave, weighed and added with 5% wt Pt-Pd/C10g,10% wt), set the hydrogenation reactor pressure at 3.0MPa, stir at 300r/min, and set the temperature at 100℃until the autoclave pressure reached 3.0MPa, and hydrogenation for 12h. After the reaction is finished, closing the heating, slowly opening a gas valve to release pressure to normal pressure when the temperature in the kettle is lower than 40 ℃, opening the kettle body, taking out the reaction liquid, adding a proper amount of diatomite for filtering, washing a filter cake with 5V methanol, merging filtrate, concentrating to obtain a crude product of moxifloxacin side chains, and rectifying the crude product to obtain 43.83g of moxifloxacin side chains (S, S) -2, 8-diazabicyclo [4,3,0] nonane VII, wherein the yield is 80%, the gas phase purity is 99.21%, and the chiral purity is 99.87%, and the result is shown in fig. 7 and 8. The nuclear magnetic resonance detection results are shown in FIG. 9.
Example 2
The preparation method comprises the following specific steps:
(1) In a 2L reaction flask, 600ml (1 v/m) of acetic anhydride was added to the 2, 3-pyridinedicarboxylic acid (500.02 g,2.99 mol) and reacted at 100℃for 2 hours. Cooling to 80 deg.c and evaporating the solvent. Adding 500ml (1 v/m) methylene dichloride into the evaporated matter, stirring for 30min at 40-45 ℃, cooling, evaporating the solvent, and repeating the steps again to obtain a ring-closing product I. The next step is directly carried out without purification;
(2) 1500ml (3 v/m) of ethylene glycol monomethyl ether is added into the evaporated matter, the temperature is reduced to-10 to-5 ℃, R-alpha-phenethylamine (398.68 g,3.29 mol) is slowly added dropwise, and the temperature is controlled between 0 ℃ and 10 ℃. After the dripping is finished, the temperature is raised to 35 ℃, and the temperature is kept for 1h. Cooling, evaporating the solvent, and completing the ring-opening reaction.
500ml (1 v/m) acetic anhydride was added to the evaporated material, and the mixture was reacted at 110℃for 3 hours, cooled to 80℃and the solvent was distilled off. 1000ml (2 v/m) of absolute ethyl alcohol is added into the evaporated-to-dryness matter, the temperature is reduced to 0-5 ℃, and the mixture is stirred for 1h. Suction filtration, rinsing the filter cake with absolute ethanol (200 ml x 3) to obtain grey crystal solid particles. Drying the mixture by an electrothermal blowing drying oven at 65 ℃ to obtain 626.73g of a ring-closed product II, wherein the yield is 91.25%, and the purity of a liquid phase is 98.35%.
(3) The ring-closed product II (502.05 g,1.99 mol) was dissolved in 3000mL of tetrahydrofuran, transferred to an autoclave, weighed and 5% wt Pd/C (51.75 g,10% wt) was added, the hydrogenation reactor pressure was set at 3MPa, the stirring speed was 300r/min, and the autoclave pressure was allowed to reach 3MPa, the temperature was set at 115℃and the hydrogenation reaction was carried out for 3 hours.
After the reaction is finished, closing the heating, when the temperature in the kettle is lower than 40 ℃, slowly opening a gas valve to release pressure to normal pressure, opening the kettle body, taking out the reaction liquid, adding a proper amount of diatomite for filtering, washing a filter cake with 5V tetrahydrofuran, merging filtrate, and concentrating to obtain a pyridine ring reduced product III 504.41g, wherein the yield is 98%.
(4) The pyridine ring reduced product III (425 g,1.65 mol) was weighed into a 5L reactor, 3L of methylene chloride was added for clearing, and then activated manganese dioxide (710 g,8.22 mol) was added in portions, and the mixture was stirred at 25℃for 12 hours. TLC control raw materials are reacted completely, the reaction is finished, the reaction liquid is filtered by diatomite, the filtrate is concentrated to obtain crude product, butyl acetate/dimethyl sulfoxide is recrystallized and purified to obtain 348.83g of olefin conjugated dicarbonyl product IV, the yield is 82.72 percent, and the liquid phase purity is 98.9 percent.
(5) Weighing an olefin conjugated dicarbonyl product IV (336.9 g,1.31 mol), placing the olefin conjugated dicarbonyl product IV in a 10L reaction kettle, adding acetonitrile 4L solution, weighing and adding 5%wt Pd/C (36 g, 10%wt), replacing three times by hydrogen balloons, carrying out reflux hydrogenation at 70 ℃ for 24 hours, controlling the raw materials to react completely in TLC, filtering the reaction liquid by kieselguhr, adding 1.6L ethanol, stirring at room temperature for 0.5 hours, maintaining the temperature at not more than 30 ℃, dropwise adding 117 mL of hydrochloric acid, cooling to 0-5 ℃ for continuously stirring for 1-2 hours, filtering a filter cake, eluting the filter cake by using 35mL of ethanol, adding the obtained filter cake into dichloromethane, adding saturated sodium bicarbonate to adjust the pH to 8-9, separating the solution, concentrating the organic phase to dryness, concentrating the filtrate to obtain a key chiral product V, recrystallizing tetrahydrofuran/ethylene glycol monomethyl ether to obtain 310.58g, and obtaining the yield 91.78%, wherein the liquid phase purity is 93.54%, and the chiral HPLC is D/L=17.27:82.73.
(6) The ring-closed product V (258.32 g,1 mol) was dissolved in 2500mL of methanol, transferred to a 5L reaction vessel, weighed and added with sodium cyanoborohydride (62.84 g,1 mol), ferric chloride (162.2 g,1 mol), stirred, and reacted at room temperature for 3h. After the reaction is finished, opening the kettle body, taking out the reaction liquid, adding a proper amount of diatomite for filtering, washing a filter cake by using frozen methanol, merging filtrate, and concentrating to obtain a carbonyl reduction product VI 225.7g, wherein the yield is 98%, and the liquid phase purity is 96.8%.
(7) Carbonyl reduction product VI (184.29 g,0.8 mol) was dissolved in 1000mL tetrahydrofuran, transferred to a 2L autoclave, weighed and Pt-Ni/C (5.53 g,10% wt) was added, the hydrogenation reactor pressure was set at 2.5MPa, the stirring speed was 300r/min, and the autoclave pressure was set at 80℃until the autoclave pressure reached 2.5MPa, and the hydrogenation reaction was carried out for 3 hours.
After the reaction is finished, closing and heating, slowly opening a gas valve to release pressure to normal pressure when the temperature in the kettle is lower than 40 ℃, opening the kettle body, taking out the reaction liquid, adding a proper amount of diatomite for filtering, washing a filter cake by using 5V tetrahydrofuran, merging filtrate, and concentrating to obtain 96.92g of moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane VII, wherein the yield is 96%, the liquid phase purity is 99.0%, and the chiral purity is 99.5%.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that modifications and adaptations to the present invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be comprehended within the scope of the present invention.
Claims (7)
1. A method for preparing moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane, comprising the steps of:
(1) Mixing the pyridine 2, 3-dicarboxylic acid SM1 and acetic anhydride, and performing cyclization reaction to obtain a ring-closing product I, wherein purification is not needed, and the next step is directly performed;
(2) Adding a solvent into a ring-closing product I, R-alpha-phenethylamine SM2, adding acetic anhydride after ring opening reaction to obtain a ring-closing product II, and directly carrying out the next step without purification;
(3) Under the condition of hydrogen, mixing the ring-closing product II, a solvent and a metal catalyst for hydrogenation reaction to obtain a pyridine ring reduced product III, and directly carrying out the next step without purification; the metal catalyst is selected from Pd/C, pd/Al 2 O 3 Or Pd (OH) 2 /C；
(4) Mixing the pyridine ring reduced product III, an oxidant and a solvent to perform selective double bond oxidation reaction to obtain an olefin conjugated dicarbonyl product IV, and recrystallizing and purifying; the oxidant is selected from manganese dioxide or/and hydrogen peroxide;
(5) Under the condition of hydrogen, mixing the olefin conjugated dicarbonyl product IV, a solvent and a metal catalyst for hydrogenation reaction to obtain a key chiral product V, and recrystallizing and purifying; the metal catalyst is selected from Pd/C, pd/Al 2 O 3 Or Pd (OH) 2 /C；
(6) Mixing the key chiral product V, a reducing agent, lewis acid and a solvent for a reduction carbonyl reaction to obtain a carbonyl reduction product VI; the reducing agent is selected from one of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and potassium borohydride; the Lewis acid is at least one or more than two selected from aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride;
(7) Under the condition of hydrogen, mixing the carbonyl reduction product VI, a solvent and a metal catalyst for deprotection to obtain the moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane VII; the metal catalyst is selected from one of Pt-Pd/C, pt-Ni/C, pd-Ni/C.
2. The method for preparing moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the solvent in the step (2) is at least one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetone, butanone and acetonitrile.
3. The method for preparing moxifloxacin side chains (S, S) -2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the solvent in the step (3) is at least one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetone, butanone and acetonitrile.
4. The method for preparing moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein in the step (4), the solvent is selected from at least one or more of tetrahydrofuran, dichloromethane, chloroform, toluene, xylene and acetonitrile.
5. The method for preparing moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the solvent in the step (5) is at least one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetone, butanone and acetonitrile.
6. The method for preparing moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the solvent in the step (6) is at least one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetone, butanone, and acetonitrile.
7. The method for preparing moxifloxacin side chain (S, S) -2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the solvent in the step (7) is at least one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, dichloromethane, petroleum ether, diethyl ether, acetone, butanone and acetonitrile.
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