CN112920184A - Method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane - Google Patents
Method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane Download PDFInfo
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- CN112920184A CN112920184A CN202110165275.0A CN202110165275A CN112920184A CN 112920184 A CN112920184 A CN 112920184A CN 202110165275 A CN202110165275 A CN 202110165275A CN 112920184 A CN112920184 A CN 112920184A
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- piperidine
- hydroxymethyl
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- 238000000034 method Methods 0.000 title claims abstract description 49
- 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 27
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound 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
- 229960003702 moxifloxacin Drugs 0.000 title claims abstract description 26
- 238000006722 reduction reaction Methods 0.000 claims abstract description 54
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 24
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 20
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 238000005984 hydrogenation reaction Methods 0.000 claims description 29
- HYRMTMLAYZSIRK-NKWVEPMBSA-N NC[C@H]1[C@@H](CO)NCCC1 Chemical compound NC[C@H]1[C@@H](CO)NCCC1 HYRMTMLAYZSIRK-NKWVEPMBSA-N 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 150000007524 organic acids Chemical class 0.000 claims description 27
- BTXRQYQPUUBFCS-NKWVEPMBSA-N NC[C@H]1[C@@H](CCl)NCCC1 Chemical compound NC[C@H]1[C@@H](CCl)NCCC1 BTXRQYQPUUBFCS-NKWVEPMBSA-N 0.000 claims description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 26
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 229910021529 ammonia Inorganic materials 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 17
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 15
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 15
- 229910052796 boron Inorganic materials 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 239000012295 chemical reaction liquid Substances 0.000 claims description 13
- 239000012320 chlorinating reagent Substances 0.000 claims description 13
- -1 halogenated nitrogen heterocyclic compound Chemical class 0.000 claims description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000003999 initiator Substances 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- USTLCLPIOPFXEV-PHDIDXHHSA-N NC([C@H]1[C@@H](CO)NCCC1)=O Chemical compound NC([C@H]1[C@@H](CO)NCCC1)=O USTLCLPIOPFXEV-PHDIDXHHSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000007098 aminolysis reaction Methods 0.000 claims description 7
- 235000019270 ammonium chloride Nutrition 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
- YZBBUYKPTHDZHF-KNVGNIICSA-N (3R)-7,2'-dihydroxy-4'-methoxyisoflavanol Chemical compound OC1=CC(OC)=CC=C1[C@H]1C(O)C2=CC=C(O)C=C2OC1 YZBBUYKPTHDZHF-KNVGNIICSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- 230000009467 reduction Effects 0.000 abstract description 6
- 238000007670 refining Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract 2
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- 239000000047 product Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 150000002431 hydrogen Chemical group 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 2
- OMJKWVKPIOIQDM-UHFFFAOYSA-N 3-bromo-1-chloroimidazolidine-2,4-dione Chemical compound ClN1CC(=O)N(Br)C1=O OMJKWVKPIOIQDM-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000010644 ester aminolysis reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 238000011085 pressure filtration Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- QDMNNMIOWVJVLY-MRVPVSSYSA-N (4s)-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1C1=CC=CC=C1 QDMNNMIOWVJVLY-MRVPVSSYSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZKLFRQSZDUSMQE-UHFFFAOYSA-N 5,5-dichloroimidazolidine-2,4-dione Chemical compound ClC1(Cl)NC(=O)NC1=O ZKLFRQSZDUSMQE-UHFFFAOYSA-N 0.000 description 1
- KHJXEDCZDBSVBE-UHFFFAOYSA-M Cl[Ir].C1CC=CCCC=C1.C1CC=CCCC=C1 Chemical class Cl[Ir].C1CC=CCCC=C1.C1CC=CCCC=C1 KHJXEDCZDBSVBE-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 150000004030 azacyclic compounds Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical group [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000003930 superacid Substances 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
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Images
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a method for preparing a moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane, and relates to the technical field of organic synthesis. According to the invention, azaphthalide is used as a raw material, due to the cyclic structure of the azaphthalide, two other non-corresponding chiral isomers which are not needed in chiral reduction can hardly be generated, the chiral purity of the reduced intermediate is very high, resolution is not needed, and (S, S) -2, 8-diazabicyclo [4,3,0] nonane can be obtained directly through ammonolysis, reduction, chlorination and cyclization. The method provided by the invention does not need chiral resolution, and has the advantages of simple process, short process steps, low cost, high chiral purity of the product and high total yield. Furthermore, in the subsequent step of salifying and refining the product, the carboxylic acid containing a chiral structure is not required to be salified, and the product purity can be further improved by refining the common achiral carboxylic acid.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a method for preparing a moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane.
Background
The moxifloxacin as a new-generation quinolone antibacterial agent has good economic value and wide market prospect, and the (S, S) -2, 8-diazabicyclo [4,3,0] nonane is an important intermediate for synthesizing the moxifloxacin. The current routes for the industrial synthesis of (S, S) -2, 8-diazabicyclo [4,3,0] nonane fall essentially into two categories: (1) the pyridine ring is reduced by palladium-carbon, and then the palladium-carbon is resolved by a chiral resolving agent, so that the total yield of the route is 30-40%, the yield is low, and the cost is high; (2) asymmetric synthesis is carried out by chiral inducing reagents, such as (S) -4-phenyl-2-oxazolidinone, which generally has complex reaction, long reaction steps and high price of the chiral inducing reagents, thus increasing the cost.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane. The method provided by the invention does not need chiral resolution, and has the advantages of simple process, short process steps, low cost, high chiral purity of the product and high total yield.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane, which comprises the following steps:
(1) carrying out hydrogenation reduction reaction on the azaphthalide under the action of a chiral catalyst and an initiator to obtain (4aR,7aS) furo [3,4-b]Piperidin-5 (1H) -one; the chiral catalyst is [ Ir (cod) Cl]2·n(R)-(+)-BINAP，n＝0.5～3；
(2) Under the protection of nitrogen, mixing the (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -ketone and an ammonia-containing compound for aminolysis reaction of ester to obtain (2S,3R) -2-hydroxymethyl piperidine-3-formamide;
(3) under the condition of nitrogen protection, mixing the (2S,3R) -2-hydroxymethyl piperidine-3-formamide with organic acid and a boron-containing reducing agent for reduction reaction to obtain (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine; the organic acid is strong organic acid or super organic acid;
(4) mixing the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine with a chlorinating reagent, heating and refluxing for chlorination reaction to obtain (2S,3S) -2-chloromethyl-3-aminomethyl piperidine;
(5) under the protection of nitrogen, carrying out cyclization reaction on the (2S,3S) -2-chloromethyl-3-aminomethyl piperidine under the action of potassium carbonate to obtain a moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane.
Preferably, the initiator in the step (1) is iodine or halogenated nitrogen heterocyclic compound, and the mass of the initiator is 0.5-30% of that of the azaphthalide; the mass of the chiral catalyst is 0.005-10% of that of the azaphthalide.
Preferably, the solvent for the hydrogenation reduction reaction in the step (1) is one or more of toluene, dioxane, benzene, xylene and tetrahydrofuran; the temperature of the hydrogenation reduction reaction is 55-70 ℃, and the pressure is 0.5-3.0 MPa.
Preferably, the ammonia-containing compound in the step (2) is one or more of urea, ammonia, ammonium chloride and ammonium acetate; the molar ratio of the (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -one to ammonia in the ammonia-containing compound is 1:1.2 to 5.0.
Preferably, the solvent for the ester ammonolysis reaction in the step (2) is one or more of N, N-dimethylformamide, toluene, xylene, N-dimethylacetamide, DMPU and DMI; the temperature of the ester ammonolysis reaction is 45-75 ℃, and the time is 3-5 h.
Preferably, the boron-containing reducing agent in the step (3) is one or more of sodium borohydride, sodium borohydride derivatives, potassium borohydride and potassium borohydride derivatives; the molar ratio of the boron-containing reducing agent to the (2S,3R) -2-hydroxymethylpiperidine-3-formamide is (0.25-1): 1; the organic acid is one or more of trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, boron trifluoride tetrahydrofuran complex and boron trifluoride diethyl etherate complex; the molar ratio of the organic acid to the boron-containing reducing agent is 0.8-4: 1.
Preferably, the solvent for the reduction reaction in the step (3) is one or more of methanol, ethanol, water, acetic acid, tetrahydrofuran and dioxane; the temperature of the reduction reaction is room temperature, and the time is 1-5 h.
Preferably, the chlorinating agent in the step (4) is one or more of N-chlorosuccinimide, chlorine, triphosgene, thionyl chloride, phosphorus oxychloride and phosphorus pentachloride; the molar ratio of the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine to the chlorinating reagent is 1: 1-2.0.
Preferably, the solvent for the chlorination reaction in the step (4) is one or more of dichloromethane, toluene, tetrahydrofuran, acetonitrile, dioxane, methyl tert-butyl ether and chloroform; the temperature of the chlorination reaction is 30-50 ℃, and the time is 2-6 h.
Preferably, the molar ratio of potassium carbonate to (2S,3S) -2-chloromethyl-3-aminomethyl piperidine in step (5) is 0.5 to 1.5: 1; the solvent of the cyclization reaction is one or more of tetrahydrofuran, an alcohol solvent, dimethylformamide and toluene; the temperature of the cyclization reaction is 55-70 ℃, and the time is 5-8 h.
Preferably, after the ring-closing reaction in step (5), the method further comprises:
filtering the obtained cyclization reaction liquid to obtain a crude product;
mixing the crude product with acid to react to form salt, and recrystallizing the obtained salt with absolute ethyl alcohol to obtain a crystal; the acid is one or more of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and oxalic acid;
dissociating the crystal with saturated sodium carbonate aqueous solution, and extracting with dichloromethane to obtain an organic phase;
and decoloring and drying the organic phase to obtain the moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane.
The invention provides a method for preparing a moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0]]A process for nonane comprising the steps of: (1) carrying out hydrogenation reduction reaction on the azaphthalide under the action of a chiral catalyst and an initiator to obtain (4aR,7aS) furo [3,4-b]Piperidin-5 (1H) -one; the chiral catalyst is [ Ir (cod) Cl]2N (r) - (+) -BINAP, n being 0.5 to 3; (2) the (4aR,7aS) furo [3,4-b ] is reacted under the protection of nitrogen]Mixing piperidine-5 (1H) -ketone and an ammonia-containing compound to carry out ester ammonolysis reaction to obtain (2S,3R) -2-hydroxymethyl piperidine-3-formamide; (3) Under the condition of nitrogen protection, mixing the (2S,3R) -2-hydroxymethyl piperidine-3-formamide with organic acid and a boron-containing reducing agent for reduction reaction to obtain (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine; the organic acid is strong organic acid or super organic acid; (4) mixing the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine with a chlorinating reagent, heating and refluxing for chlorination reaction to obtain (2S,3S) -2-chloromethyl-3-aminomethyl piperidine; (5) under the protection of nitrogen, the (2S,3S) -2-chloromethyl-3-aminomethyl piperidine is subjected to cyclization reaction under the action of potassium carbonate to obtain a moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0]Nonane. According to the invention, azaphthalide is used as a raw material, due to the cyclic structure of the azaphthalide, two other non-corresponding chiral isomers which are not needed in chiral reduction (namely hydrogenation reduction reaction) are hardly generated, the chiral purity of the reduced intermediate is very high, the intermediate is not required to be split, and the moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3, 0-can be obtained by aminolysis, reduction, chlorination and cyclization directly]Nonane. The method provided by the invention does not need chiral resolution, and has the advantages of simple process, short process steps, low cost, high chiral purity of the product and high total yield.
Furthermore, in the subsequent step of salifying and refining the product, the carboxylic acid containing a chiral structure is not required to be salified, and the product purity can be further improved by refining the common achiral carboxylic acid (one or more of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and oxalic acid).
The results of the examples show that the method for preparing the moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane has the yield of 82%, the chemical purity of the product of 99.8% and the chiral purity of 99.5%.
Drawings
FIG. 1 is a nuclear magnetic spectrum of the product prepared in example 1.
Detailed Description
The invention provides a method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane, which comprises the following steps:
(1) carrying out hydrogenation reduction reaction on the azaphthalide under the action of a chiral catalyst and an initiator to obtain (4aR,7aS) furo [3,4-b]Piperidin-5 (1H) -one; the chiral catalyst is [ Ir (cod) Cl]2·n(R)-(+)-BINAP，n＝0.5～3；
(2) Under the protection of nitrogen, mixing the (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -ketone and an ammonia-containing compound for aminolysis reaction of ester to obtain (2S,3R) -2-hydroxymethyl piperidine-3-formamide;
(3) under the condition of nitrogen protection, mixing the (2S,3R) -2-hydroxymethyl piperidine-3-formamide with organic acid and a boron-containing reducing agent for reduction reaction to obtain (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine; the organic acid is strong organic acid or super organic acid;
(4) mixing the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine with a chlorinating reagent, heating and refluxing for chlorination reaction to obtain (2S,3S) -2-chloromethyl-3-aminomethyl piperidine;
(5) under the protection of nitrogen, carrying out cyclization reaction on the (2S,3S) -2-chloromethyl-3-aminomethyl piperidine under the action of potassium carbonate to obtain a moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane.
The invention carries out hydrogenation reduction reaction on aza-phthalide (a compound shown in formula 2) under the action of a chiral catalyst and an initiator to obtain (4aR,7aS) furo [3,4-b ]]Piperidine-5 (1H) -ketone (compound shown in formula 3). In the present invention, the initiator is preferably iodine or a halogenated azacyclic compound, preferably MCDMH (bromochlorohydantoin), DCDMH (dichlorohydantoin) or TCCA (trichloroisocyanuric acid); the mass of the initiator is preferably 0.5-30% of that of the azaphthalide, and more preferably 1-10%. In the present invention, the chiral catalyst is [ Ir (cod) Cl]2N (R) - (+) -BINAP, n is 0.5-3, preferably 1-2, i.e. the chiral catalyst is an iridium catalyst [ Ir (cod) Cl]2And chiral phosphorus ligand (R) - (+) -BINAP at a molar ratio of 1: 0.5-3 (note: chiral catalyst [ Ir (cod) Cl)]2Bis (1, 5-cyclooctadiene) iridium (I) chloride dimer, (R) - (+) -BINAP means (R) - (+) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl); the chiral catalyst is preferably of a massIs 0.005 to 10% by mass, more preferably 0.005 to 1% by mass, based on the azaphthalide; the source of the chiral catalyst is not particularly critical in the present invention and can be prepared by itself using commercially available products well known to those skilled in the art or by methods well known to those skilled in the art. In the invention, the solvent for the hydrogenation reduction reaction is preferably one or more of toluene, dioxane, benzene, xylene and tetrahydrofuran, and the mass of the solvent is preferably 2-10 times of that of azaphthalide. In the invention, the pressure of the hydrogenation reduction reaction is preferably 0.5-3.0 MPa, and more preferably 1.5-2.0 MPa; the temperature of the hydrogenation reduction reaction is preferably 55-70 ℃, and more preferably 60-65 ℃; in the present invention, the time of the hydrogenation reduction reaction is judged as a criterion that the pressure does not drop within 1 hour, that is, the hydrogenation reduction reaction is considered to be completed when the pressure does not drop within 1 hour. In the present invention, the hydrogenation reduction reaction is preferably carried out in a stainless steel autoclave. In the present invention, the reaction formula of the hydrogenation reduction reaction is:
in the present invention, the specific operation of the hydrogenation reduction reaction is preferably: dissolving the azaphthalide by using a solvent, replacing the solution by using nitrogen for three times, and then replacing the solution by using hydrogen; then adding the chiral catalyst and the initiator into the obtained azaphthalide solution, and then replacing by hydrogen; and raising the temperature of the obtained system to 55-70 ℃, and pressurizing to 0.5-3.0 MPa for hydrogenation reduction reaction.
After the hydrogenation reduction reaction is finished, the invention preferably carries out post-treatment on the obtained hydrogenation reduction reaction liquid; the method of post-treatment is preferably: filter-pressing the obtained hydrogenation reduction reaction liquid into a common reaction kettle, washing the hydrogenation reduction reaction liquid with a saturated sodium bicarbonate aqueous solution, separating a lower water layer, and collecting an organic layer; and refluxing the organic layer for 1-2 hours with water, then recovering solvents such aS toluene and the like in the organic layer, and obtaining (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -ketone after the recovery is finished. In the invention, the method for washing the hydrogenation reduction reaction solution by using the saturated sodium bicarbonate aqueous solution comprises the following specific steps: adding a saturated sodium bicarbonate aqueous solution into the hydrogenation reduction reaction solution, stirring, standing for layering, and removing a lower water layer; the number of washing is preferably 2. In the present invention, the method for recovering a solvent such as toluene in the organic layer specifically includes: and distilling the organic layer at normal pressure and then distilling the organic layer at reduced pressure.
After (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -ketone is obtained, the (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -ketone and an ammonia-containing compound are mixed under the protection of nitrogen gas to carry out ester aminolysis reaction, so aS to obtain (2S,3R) -2-hydroxymethyl piperidine-3-formamide (a compound shown in a formula 4). In the invention, the ammonia compound is preferably one or more of urea, ammonia, ammonium chloride and ammonium acetate, more preferably ammonia, the ammonia comprises liquid ammonia or ammonia water, and the mass concentration of the ammonia water is preferably 30%; the molar ratio of the (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -one to ammonia in the ammonia-containing compound is preferably 1:1.2 to 5.0, more preferably 1:2 to 4. In the invention, the solvent for the ester ammonolysis reaction is preferably one or more of N, N-Dimethylformamide (DMF), toluene, xylene, N-dimethylacetamide, DMPU and DMI, and the mass of the solvent is preferably 2-15 times of that of (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -one. In the invention, the temperature of the ester ammonolysis reaction is preferably 45-75 ℃, more preferably 50-65 ℃, and the time is preferably 3-5 h, more preferably 3.5-4.5 h; the aminolysis of the ester is preferably carried out under micropressure conditions, the pressure of the micropressure preferably being less than one atmosphere. In the present invention, the reaction formula of the aminolysis reaction of the ester is:
in the present invention, the specific operation of the aminolysis reaction of the ester is preferably: under the condition of nitrogen protection, dissolving (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -ketone in the solvent to obtain a (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -ketone solution; slowly adding an ammonia-containing compound into the (4aR,7aS) furo [3,4-b ] piperidine-5 (1H) -ketone solution, and then heating the system to 45-75 ℃ to carry out ester aminolysis reaction. In the present invention, the feeding rate of the ammonia-containing compound is preferably such that no flushing and no large temperature fluctuation occur.
After the ammonolysis reaction of the ester is finished, the invention preferably carries out post-treatment on the obtained ammonolysis reaction liquid; the method of post-treatment is preferably: filter-pressing the obtained ammonolysis reaction liquid into an ammonium chloride solution for quenching, then extracting by using methyl tert-butyl ether, and collecting a methyl tert-butyl ether layer; and (2S,3R) -2-hydroxymethyl piperidine-3-formamide is obtained by sequentially washing and drying the methyl tert-butyl ether layer and then distilling to remove the methyl tert-butyl ether layer. In the present invention, the mass concentration of the ammonium chloride solution is preferably 10%.
After obtaining (2S,3R) -2-hydroxymethyl piperidine-3-formamide, mixing the (2S,3R) -2-hydroxymethyl piperidine-3-formamide with organic acid and boron-containing reducing agent under the condition of nitrogen protection to carry out reduction reaction to obtain (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine (a compound shown in a formula 5); the organic acid is strong organic acid or super organic acid. In the invention, the boron-containing reducing agent is preferably one or more of sodium borohydride, sodium borohydride derivatives (such as sodium triacetoxyborohydride, sodium triethylborohydride and sodium tris (1-pyrazolyl) borohydride), potassium borohydride and potassium borohydride derivatives (such as potassium triphenylborohydride, potassium triisopropoxyborohydride and potassium triethylborohydride), and more preferably sodium borohydride; the molar ratio of the boron-containing reducing agent to the (2S,3R) -2-hydroxymethylpiperidine-3-carboxamide is preferably 0.25-1: 1, more preferably 0.5 to 0.8: 1. in the present invention, the organic acid is preferably one or more of trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, boron trifluoride tetrahydrofuran complex and boron trifluoride diethyl etherate complex (in the present invention, trifluoromethanesulfonic acid is an organic superacid, and trifluoroacetic acid, acetic acid, boron trifluoride tetrahydrofuran complex and boron trifluoride diethyl etherate complex are organic strong acids), more preferably boron trifluoride tetrahydrofuran complex; the molar ratio of the organic acid to the boron-containing reducing agent is preferably 0.8-4: 1, and more preferably 1-3: 1. In the invention, the solvent for the reduction reaction is preferably one or more of methanol, ethanol, water, acetic acid, tetrahydrofuran and dioxane; the mass of the solvent is preferably 2-15 times of that of (2S,3R) -2-hydroxymethylpiperidine-3-formamide. In the invention, the temperature of the reduction reaction is preferably room temperature, and the time is preferably 1-5 h, and more preferably 2 h. In the present invention, the reaction is preferably terminated by adding acetic acid after the reduction reaction is completed. In the present invention, the reaction formula of the reduction reaction is:
in the present invention, the specific operation of the reduction reaction is preferably: under the protection of nitrogen, adding the solvent and the organic acid into (2S,3R) -2-hydroxymethylpiperidine-3-formamide for dissolving to obtain a mixed solution; adding a boron-containing reducing agent into the mixed solution in batches, carrying out reduction reaction under the stirring condition, and adding acetic acid to terminate the reaction after the reaction is finished.
After the reduction reaction, in the present invention, it is preferable to recover the solvent by distilling the obtained reduction reaction solution under reduced pressure to obtain (2S,3S) -2-hydroxymethyl-3-aminomethylpiperidine.
After obtaining (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine, the invention mixes the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine with a chlorinating agent, and performs a chlorination reaction by heating and refluxing to obtain (2S,3S) -2-chloromethyl-3-aminomethyl piperidine (a compound shown in formula 6). In the invention, the chlorinating agent is preferably one or more of N-chlorosuccinimide (NCS), chlorine, triphosgene, thionyl chloride, phosphorus oxychloride and phosphorus pentachloride, and is more preferably N-chlorosuccinimide; the molar ratio of the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine to the chlorinating agent is preferably 1: 1-2.0, and more preferably 1: 1.2-1.5. In the invention, the solvent for the chlorination reaction is preferably one or more of dichloromethane, toluene, tetrahydrofuran, acetonitrile, dioxane, methyl tert-butyl ether and chloroform, and more preferably dichloromethane; the mass of the solvent is preferably 2-15 times of that of (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine. In the invention, the temperature of the chlorination reaction (i.e. the temperature of heating reflux) is preferably 30-50 ℃, more preferably 40 ℃, and the time is preferably 2-6 h, more preferably 3 h. In the present invention, the reaction formula of the chlorination reaction is:
in the present invention, the specific operation of the chlorination reaction is preferably: dissolving (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine in the solvent to obtain a (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine solution; adding a chlorinating reagent into the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine solution in batches, and then heating the system to the reflux temperature for chlorination reaction. In the embodiment of the invention, the chlorinating agent is preferably added in 3-5 times.
After the chlorination reaction, the invention preferably washes the obtained chlorination reaction liquid with saturated sodium bicarbonate water solution, separates out the water layer, and collects the organic layer; and (2S,3S) -2-chloromethyl-3-aminomethyl piperidine is obtained after the solvent in the organic layer is recovered (atmospheric distillation and then reduced pressure distillation).
After obtaining (2S,3S) -2-chloromethyl-3-aminomethyl piperidine, under the protection of nitrogen, the invention performs cyclization reaction on the (2S,3S) -2-chloromethyl-3-aminomethyl piperidine under the action of potassium carbonate to obtain a moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane (a compound shown in a formula 1). In the present invention, the molar ratio of the potassium carbonate to the (2S,3S) -2-chloromethyl-3-aminomethyl piperidine is preferably 0.5 to 1.5: 1, more preferably 0.8-1.3: 1; the potassium carbonate is both a catalyst and an acid-binding agent. In the invention, the solvent for the cyclization reaction is preferably one or more of tetrahydrofuran, an alcohol solvent, dimethylformamide and toluene, and more preferably tetrahydrofuran; the mass of the solvent is preferably 2-15 times of that of (2S,3S) -2-chloromethyl-3-aminomethyl piperidine. In the invention, the temperature of the cyclization reaction is preferably 55-70 ℃, and more preferably 60-65 ℃; the time is preferably 5-8 h, and more preferably 6 h. In the present invention, the cyclization reaction has the reaction formula:
in the present invention, the specific operation of the cyclization reaction is preferably: under the protection of nitrogen, dissolving (2S,3S) -2-chloromethyl-3-aminomethyl piperidine in the solvent to obtain a (2S,3S) -2-chloromethyl-3-aminomethyl piperidine solution; adding potassium carbonate into the (2S,3S) -2-chloromethyl-3-aminomethyl piperidine solution in batches, heating the system to 55-70 ℃, and carrying out cyclization reaction under the stirring condition. In the embodiment of the invention, the potassium carbonate is preferably added in 3-5 times.
After the cyclization reaction, the present invention also preferably comprises:
filtering the obtained cyclization reaction liquid to obtain a crude product;
mixing the crude product with acid to react to form salt, and recrystallizing the obtained salt with absolute ethyl alcohol to obtain a crystal; the acid is one or more of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and oxalic acid;
dissociating the crystal with saturated sodium carbonate aqueous solution, and extracting with dichloromethane to obtain an organic phase;
and decoloring and drying the organic phase to obtain the moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane.
The method of filtration is not particularly required in the present invention, and a filtration method known to those skilled in the art may be used. In the invention, the molar ratio of the (2S,3S) -2-chloromethyl-3-aminomethyl piperidine to the acid is preferably 1: 1-2; the time for the reaction to form the salt is preferably 1 hour; the acid and the crude product are salified and solidified into solid, so that recrystallization is facilitated, and a product with higher purity is obtained. In the present invention, taking an acid as p-toluenesulfonic acid as an example, the reaction formula of the acid and the crude product for salt formation is as follows (a compound represented by formula 7 is a salt former, wherein TsOH represents p-toluenesulfonic acid):
the present invention does not require any particular method for carrying out the recrystallization, and any method known to those skilled in the art may be used. In the invention, the method for dissociating the crystal by using the saturated sodium carbonate aqueous solution specifically comprises the following steps: and (3) dropwise adding saturated sodium carbonate aqueous solution into the crystal, reacting sodium carbonate with acid (namely, acid-base neutralization reaction), and converting the salt-forming product into a monomer (namely, converting the compound shown in the formula 7 into the compound shown in the formula 1). In the invention, the dichloromethane is added into the mixed solution obtained after the saturated sodium carbonate aqueous solution is dissociated for extraction. In the present invention, the decoloring agent for decoloring is preferably activated carbon, and the drying agent is preferably anhydrous sodium sulfate. In the step of salifying and refining the product, the carboxylic acid with a chiral structure is not required to be used for salifying, and the ordinary achiral carboxylic acid p-toluenesulfonic acid can be used for refining to further improve the purity of the product.
The method provided by the invention does not need chiral resolution, and has the advantages of simple process, short process steps, low cost, high chiral purity of the product and high total yield.
The following examples are provided to illustrate the method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane according to the present invention, but they should not be construed as limiting the scope of the present invention.
Example 1
The moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane is prepared by the following method:
(1) (4aR,7aS) furo [3,4-b]Preparation of piperidin-5 (1H) -one: 40g of azaphthalide was dissolved in 100mL of toluene in a 250mL autoclave, replaced with nitrogen three times, then replaced with hydrogen, and 0.002g of a chiral catalyst ([ Ir (cod) Cl) was added]22(R) - (+) -BINAP) and 1g of iodine were replaced with hydrogen, the temperature was raised to 65 ℃ and the pressure was increased to 1.5MPa to conduct hydrogenation reduction. After the reaction is finished, the obtained hydrogenation reduction reaction liquid is filter-pressed to a common reaction kettle, washed for 2 times by saturated sodium bicarbonate water solution, refluxed with water for 2 hours, then recovered with toluene, and recovered to obtain (4aR,7aS) furo [3,4-b ]]Piperidine-5 (1H) -one, under nitrogen protection, was dissolved in 200mL of DMFAnd (4) dissolving, and directly using for the next reaction.
(2) Preparation of (2S,3R) -2-hydroxymethylpiperidine-3-carboxamide: under the protection of nitrogen, 50g of ammonia water (30 wt%) is slowly added into a DMF solution of (4aR,7aS) furo [3,4-b ] piperidine-5 (1H) -ketone obtained in the step (1), the temperature is raised to 50 ℃ for ammonolysis reaction, the reaction is carried out under the condition of micro-pressure heat preservation for 5 hours, the reaction is finished, the obtained ammonolysis reaction liquid is subjected to pressure filtration to 100mL of 10 wt% ammonium chloride solution, then methyl tert-butyl ether is used for extraction, washing and drying are carried out, and methyl tert-butyl ether is recovered, so that (2S,3R) -2-hydroxymethylpiperidine-3-formamide is obtained.
(3) Preparation of (2S,3S) -2-hydroxymethyl-3-aminomethylpiperidine: adding 200mL of methanol and 3mL of boron trifluoride tetrahydrofuran complex into a reaction kettle containing (2S,3R) -2-hydroxymethyl piperidine-3-formamide for dissolving, adding sodium borohydride in batches under the protection of nitrogen for reduction reaction, stirring for 2 hours after the addition is finished, sampling, confirming that the reaction is complete, adding a small amount of acetic acid, and stirring for 10 minutes; then, the resulting reduction reaction solution was distilled under reduced pressure to recover methanol to give (2S,3S) -2-hydroxymethyl-3-aminomethylpiperidine, which was dissolved in 250mL of dichloromethane.
(4) Preparation of (2S,3S) -2-chloromethyl-3-aminomethylpiperidine: adding NCS in batches into dichloromethane solution of (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine, heating to 40 ℃ after adding, refluxing for 3 hours for chlorination reaction, sampling TLC, completely reacting (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine, washing once with 200mL of saturated sodium bicarbonate aqueous solution, and recovering the solvent to obtain (2S,3S) -2-chloromethyl-3-aminomethyl piperidine.
(5) Preparation of (S, S) -2, 8-diazabicyclo [4,3,0] nonane p-toluenesulfonate: under the protection of nitrogen, (2S,3S) -2-chloromethyl-3-aminomethyl piperidine is dissolved by 100mL tetrahydrofuran, then 32g of potassium carbonate is added in batches, the temperature is raised to 70 ℃ for cyclization reaction, and the mixture is stirred for 6 hours after the addition, sampled and confirmed to be completely reacted; and then filtering out a solid, adding p-toluenesulfonic acid, stirring at room temperature for 1 hour, recovering the solvent, and then recrystallizing with absolute ethanol to obtain a salt-forming crystal, wherein the purity is over 99.5% by HPLC (high performance liquid chromatography) detection (detection requires derivatization).
(6) Preparation of (S, S) -2, 8-diazabicyclo [4,3,0] nonane: dissociating the salifying crystal obtained in the step (5) by using a saturated sodium carbonate aqueous solution, extracting by using 200mL of dimethyl alkane, decoloring and drying by using 1g of activated carbon and 2g of anhydrous sodium sulphate, filtering, and evaporating to dryness to obtain 22.1g of moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane. The yield is 82%, the chemical purity is 99.8%, and the chiral purity is 99.5%. The nuclear magnetic confirmation data are as follows (see fig. 1 for nuclear magnetic spectrum):
1HNMR(400MHz,Chloroform-d)δ3.10(td,J＝4.6,1.5Hz,1H),2.99–2.80(m,4H),2.71(dd,J＝11.3,1.5Hz,1H),2.55(ddd,J＝12.1,11.0,2.9Hz,1H),2.08–1.96(m,1H),1.85(s,2H),1.68–1.58(m,2H),1.58–1.42(m,1H),1.42–1.30(m,1H).
example 2
The moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane is prepared by the following method:
(1) (4aR,7aS) furo [3,4-b]Preparation of piperidin-5 (1H) -one: 40g of azaphthalide was dissolved in 100mL of toluene in a 250mL autoclave, replaced with nitrogen three times, then replaced with hydrogen, and 0.002g of a chiral catalyst ([ Ir (cod) Cl) was added]2Replacing (R) - (+) -BINAP) and 0.5g bromochlorohydantoin with hydrogen, heating to 70 ℃, and pressurizing to 1.7MPa for hydrogenation reduction. After the reaction is finished, the obtained hydrogenation reduction reaction liquid is filter-pressed to a common reaction kettle, washed for 2 times by saturated sodium bicarbonate water solution, refluxed with water for 2 hours, then recovered with toluene, and recovered to obtain (4aR,7aS) furo [3,4-b ]]Piperidin-5 (1H) -one was dissolved in 200mL of DMF under nitrogen protection and used as it was in the next reaction.
(2) Preparation of (2S,3R) -2-hydroxymethylpiperidine-3-carboxamide: under the protection of nitrogen, 20g of ammonium acetate (30 wt%) is slowly added into a DMF solution of (4aR,7aS) furo [3,4-b ] piperidine-5 (1H) -ketone obtained in the step (1), the temperature is raised to 70 ℃ for ammonolysis reaction, the reaction is carried out under the condition of micro-pressure heat preservation for 6 hours, the reaction is finished, the obtained ammonolysis reaction liquid is subjected to pressure filtration to 100mL of 10 wt% ammonium chloride solution, then methyl tert-butyl ether is used for extraction, washing and drying are carried out, and methyl tert-butyl ether is recovered, so that (2S,3R) -2-hydroxymethylpiperidine-3-formamide is obtained.
(3) Preparation of (2S,3S) -2-hydroxymethyl-3-aminomethylpiperidine: adding 200mL of methanol and 2mL of trifluoroacetic acid into a reaction kettle containing (2S,3R) -2-hydroxymethylpiperidine-3-formamide, adding 0.25eq of sodium borohydride in batches under the protection of nitrogen gas for reduction reaction, stirring for 3 hours after the addition is finished, sampling, confirming that the reaction is complete, adding a small amount of acetic acid, and stirring for 10 minutes; then, the resulting reduction reaction solution was distilled under reduced pressure to recover methanol to give (2S,3S) -2-hydroxymethyl-3-aminomethylpiperidine, which was dissolved in 250mL of dichloromethane.
(4) Preparation of (2S,3S) -2-chloromethyl-3-aminomethylpiperidine: adding 25g of triphosgene into a dichloromethane solution of (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine in batches, heating to 45 ℃ after adding, refluxing for 2.5 hours to perform chlorination reaction, sampling TLC, completely reacting (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine, washing once with 200mL of saturated sodium bicarbonate aqueous solution, and recovering a solvent to obtain (2S,3S) -2-chloromethyl-3-aminomethyl piperidine.
(5) Preparation of (S, S) -2, 8-diazabicyclo [4,3,0] nonane oxalate: under the protection of nitrogen, (2S,3S) -2-chloromethyl-3-aminomethyl piperidine is dissolved by 100mL tetrahydrofuran, then 32g of potassium carbonate is added in batches, the temperature is raised to 70 ℃ for cyclization reaction, and the mixture is stirred for 6 hours after the addition, sampled and confirmed to be completely reacted; and then filtering out a solid, adding oxalic acid, stirring at room temperature for 1 hour, recovering the solvent, then recrystallizing with absolute ethyl alcohol to obtain a salt-forming crystal, wherein the purity is over 99.5 percent (the detection needs derivatization) by HPLC detection.
(6) Preparation of (S, S) -2, 8-diazabicyclo [4,3,0] nonane: dissociating the salifying crystal obtained in the step (5) by using a saturated sodium carbonate aqueous solution, extracting by using 200mL of dimethyl alkane, decoloring and drying by using 1g of activated carbon and 2g of anhydrous sodium sulphate, filtering, and evaporating to dryness to obtain 20.5g of moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane. The yield is 76%, the chemical purity is 99.0%, and the chiral purity is 99.3%.
The method provided by the invention does not need chiral resolution, and has the advantages of simple process, short process steps, low cost, high chiral purity of the product and high total yield.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A process for the preparation of moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane, characterized in that it comprises the following steps:
(1) carrying out hydrogenation reduction reaction on the azaphthalide under the action of a chiral catalyst and an initiator to obtain (4aR,7aS) furo [3,4-b]Piperidin-5 (1H) -one; the chiral catalyst is [ Ir (cod) Cl]2·n(R)-(+)-BINAP，n＝0.5～3；
(2) Under the protection of nitrogen, mixing the (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -ketone and an ammonia-containing compound for aminolysis reaction of ester to obtain (2S,3R) -2-hydroxymethyl piperidine-3-formamide;
(3) under the condition of nitrogen protection, mixing the (2S,3R) -2-hydroxymethyl piperidine-3-formamide with organic acid and a boron-containing reducing agent for reduction reaction to obtain (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine; the organic acid is strong organic acid or super organic acid;
(4) mixing the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine with a chlorinating reagent, heating and refluxing for chlorination reaction to obtain (2S,3S) -2-chloromethyl-3-aminomethyl piperidine;
(5) under the protection of nitrogen, carrying out cyclization reaction on the (2S,3S) -2-chloromethyl-3-aminomethyl piperidine under the action of potassium carbonate to obtain a moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane.
2. The method according to claim 1, wherein the initiator in the step (1) is iodine or halogenated nitrogen heterocyclic compound, and the mass of the initiator is 0.5-30% of that of the azaphthalide; the mass of the chiral catalyst is 0.005-10% of that of the azaphthalide;
the solvent for the hydrogenation reduction reaction is one or more of toluene, dioxane, benzene, xylene and tetrahydrofuran; the temperature of the hydrogenation reduction reaction is 55-70 ℃, and the pressure is 0.5-3.0 MPa.
3. The method according to claim 1, wherein the ammonia-containing compound in step (2) is one or more of urea, ammonia, ammonium chloride and ammonium acetate; the molar ratio of the (4aR,7aS) furo [3,4-b ] piperidin-5 (1H) -one to ammonia in the ammonia-containing compound is 1:1.2 to 5.0.
4. The method according to claim 1, wherein the solvent for the ammonolysis reaction of the ester in the step (2) is one or more of N, N-dimethylformamide, toluene, xylene, N-dimethylacetamide, DMPU and DMI; the temperature of the ester ammonolysis reaction is 45-75 ℃, and the time is 3-5 h.
5. The method according to claim 1, wherein the boron-containing reducing agent in step (3) is one or more of sodium borohydride, sodium borohydride derivatives, potassium borohydride and potassium borohydride derivatives; the molar ratio of the boron-containing reducing agent to the (2S,3R) -2-hydroxymethylpiperidine-3-formamide is (0.25-1): 1; the organic acid is one or more of trifluoroacetic acid, acetic acid, trifluoromethanesulfonic acid, boron trifluoride tetrahydrofuran complex and boron trifluoride diethyl etherate complex; the molar ratio of the organic acid to the boron-containing reducing agent is 0.8-4: 1.
6. The method according to claim 1, wherein the solvent for the reduction reaction in step (3) is one or more of methanol, ethanol, water, acetic acid, tetrahydrofuran and dioxane; the temperature of the reduction reaction is room temperature, and the time is 1-5 h.
7. The method according to claim 1, wherein the chlorinating agent in the step (4) is one or more of N-chlorosuccinimide, chlorine gas, triphosgene, thionyl chloride, phosphorus oxychloride and phosphorus pentachloride; the molar ratio of the (2S,3S) -2-hydroxymethyl-3-aminomethyl piperidine to the chlorinating reagent is 1: 1-2.0.
8. The method according to claim 1, wherein the solvent for the chlorination reaction in step (4) is one or more of dichloromethane, toluene, tetrahydrofuran, acetonitrile, dioxane, methyl tert-butyl ether and chloroform; the temperature of the chlorination reaction is 30-50 ℃, and the time is 2-6 h.
9. The method according to claim 1, wherein the molar ratio of potassium carbonate to (2S,3S) -2-chloromethyl-3-aminomethylpiperidine in step (5) is 0.5 to 1.5: 1; the solvent of the cyclization reaction is one or more of tetrahydrofuran, an alcohol solvent, dimethylformamide and toluene; the temperature of the cyclization reaction is 55-70 ℃, and the time is 5-8 h.
10. The method according to claim 1 or 9, wherein after the cyclization reaction in step (5), the method further comprises:
filtering the obtained cyclization reaction liquid to obtain a crude product;
reacting the crude product with acid to form salt, and recrystallizing the obtained salt with absolute ethyl alcohol to obtain a crystal; the acid is one or more of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and oxalic acid;
dissociating the crystal with saturated sodium carbonate aqueous solution, and extracting with dichloromethane to obtain an organic phase;
and decoloring and drying the organic phase to obtain the moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408427A (en) * | 2011-10-22 | 2012-04-11 | 浙江普洛康裕制药有限公司 | Preparation method of moxifloxacin intermediate [ 1S, 6R ] -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0 ] nonane |
| CN102746294A (en) * | 2011-10-12 | 2012-10-24 | 郭峰 | Preparation method of (S,S)-2,8-diazabicyclo[4.3.0] |
| CN102952130A (en) * | 2011-08-24 | 2013-03-06 | 重庆华邦胜凯制药有限公司 | Method for chiral synthesis of (S,S)-2-8-diazabicyclononane |
| CN103183673A (en) * | 2011-12-30 | 2013-07-03 | 浙江新和成股份有限公司 | Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane |
| CN105153155A (en) * | 2015-09-18 | 2015-12-16 | 华东师范大学 | Preparation method for 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo-[3,4-b] pyridine |
| CN105566319A (en) * | 2014-10-09 | 2016-05-11 | 和鼎（南京）医药技术有限公司 | Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane |
| CN108623583A (en) * | 2018-05-04 | 2018-10-09 | 新乡学院 | A kind of preparation method of the moxifloxacin side chain intermediate of iridium catalysis |
| CN110317201A (en) * | 2019-07-31 | 2019-10-11 | 武汉理工大学 | The method of asymmetric synthesis of (S, S) -2,8- diazabicyclo [4,3,0] nonane |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1393337B1 (en) * | 2009-03-06 | 2012-04-20 | Italiana Sint Spa | SUMMARY OF (4AS, 7AS) -OTTAIDRO-1H-PIRROLO [3,4-B] PYRIDINE |
| CN103044418B (en) * | 2011-10-14 | 2015-02-04 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane |
| CN107686852B (en) * | 2016-08-04 | 2022-08-02 | 上海朴颐化学科技有限公司 | Preparation method of moxifloxacin intermediate compound |
| CN112939849B (en) * | 2019-12-11 | 2022-05-03 | 浙江新和成股份有限公司 | (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof |
| IN202023007365A (en) * | 2020-02-20 | 2021-08-27 | Aarti Industries Limited | |
| CN112920184B (en) * | 2021-02-06 | 2022-03-01 | 台州市生物医化产业研究院有限公司 | Method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane |
| CN112939847B (en) * | 2021-02-06 | 2022-05-13 | 台州市生物医化产业研究院有限公司 | Method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane |
-
2021
- 2021-02-06 CN CN202110165275.0A patent/CN112920184B/en active Active
- 2021-12-18 WO PCT/CN2021/139394 patent/WO2022166436A1/en active Application Filing
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102952130A (en) * | 2011-08-24 | 2013-03-06 | 重庆华邦胜凯制药有限公司 | Method for chiral synthesis of (S,S)-2-8-diazabicyclononane |
| CN102746294A (en) * | 2011-10-12 | 2012-10-24 | 郭峰 | Preparation method of (S,S)-2,8-diazabicyclo[4.3.0] |
| CN102408427A (en) * | 2011-10-22 | 2012-04-11 | 浙江普洛康裕制药有限公司 | Preparation method of moxifloxacin intermediate [ 1S, 6R ] -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0 ] nonane |
| CN103183673A (en) * | 2011-12-30 | 2013-07-03 | 浙江新和成股份有限公司 | Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane |
| CN105566319A (en) * | 2014-10-09 | 2016-05-11 | 和鼎（南京）医药技术有限公司 | Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane |
| CN105153155A (en) * | 2015-09-18 | 2015-12-16 | 华东师范大学 | Preparation method for 6-benzyl-5,7-dioxo-1,2,3,4-tetrahydro-pyrrolo-[3,4-b] pyridine |
| CN108623583A (en) * | 2018-05-04 | 2018-10-09 | 新乡学院 | A kind of preparation method of the moxifloxacin side chain intermediate of iridium catalysis |
| CN110317201A (en) * | 2019-07-31 | 2019-10-11 | 武汉理工大学 | The method of asymmetric synthesis of (S, S) -2,8- diazabicyclo [4,3,0] nonane |
Non-Patent Citations (1)
| Title |
|---|
| 田朝爽: "手性化合物(S,S)-2,8-二氮杂双环[4.3.0]壬烷的合成研究", 《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022166436A1 (en) * | 2021-02-06 | 2022-08-11 | 台州市生物医化产业研究院有限公司 | Method for preparing moxifloxacin intermediate (s, s)-2, 8-diazabicyclo [4, 3, 0] nonane |
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