CN109096276A - The preparation method of moxifloxacin hydrochloride and its intermediate - Google Patents
The preparation method of moxifloxacin hydrochloride and its intermediate Download PDFInfo
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- CN109096276A CN109096276A CN201810864847.2A CN201810864847A CN109096276A CN 109096276 A CN109096276 A CN 109096276A CN 201810864847 A CN201810864847 A CN 201810864847A CN 109096276 A CN109096276 A CN 109096276A
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- Prior art keywords
- moxifloxacin hydrochloride
- preparation
- hydrochloride intermediate
- intermediate iii
- moxifloxacin
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- 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 title claims abstract description 188
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 title claims abstract description 188
- 238000002360 preparation method Methods 0.000 title claims abstract description 123
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- 238000006482 condensation reaction Methods 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 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 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims description 67
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 44
- 238000003756 stirring Methods 0.000 claims description 30
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- -1 1- cyclopropyl Chemical group 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 229960003702 moxifloxacin Drugs 0.000 claims description 21
- 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 claims description 21
- 238000001914 filtration Methods 0.000 claims description 20
- 239000007789 gas Substances 0.000 claims description 20
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 20
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 20
- 239000012043 crude product Substances 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 14
- 150000001298 alcohols Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- 230000001681 protective effect Effects 0.000 claims description 10
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000002825 nitriles Chemical group 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 238000012805 post-processing Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 claims 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- 239000000463 material Substances 0.000 abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 235000019441 ethanol Nutrition 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000001291 vacuum drying Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 239000000356 contaminant Substances 0.000 description 8
- 150000008282 halocarbons Chemical class 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000005360 mashing Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 231100000004 severe toxicity Toxicity 0.000 description 3
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 101710183280 Topoisomerase Proteins 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 150000001638 boron Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- AIDQCFHFXWPAFG-UHFFFAOYSA-N n-formylformamide Chemical compound O=CNC=O AIDQCFHFXWPAFG-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- KSCPLKVBWDOSAI-UHFFFAOYSA-N 2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCCC2CNCC21 KSCPLKVBWDOSAI-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- YCAZALSUJDPQPP-UHFFFAOYSA-N 4-oxo-3h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)C=NC2=C1 YCAZALSUJDPQPP-UHFFFAOYSA-N 0.000 description 1
- 206010001076 Acute sinusitis Diseases 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 1
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 150000003952 β-lactams Chemical class 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses the preparation methods of moxifloxacin hydrochloride and its intermediate.The present invention provides the preparation methods of moxifloxacin hydrochloride intermediate III a kind of, the following steps are included: in organic solvent, in the presence of alkali, by moxifloxacin hydrochloride intermediate II and (S, S) -2,8- diazabicyclo [4,3,0] nonane carries out condensation reaction, obtains moxifloxacin hydrochloride intermediate III.Preparation method of the invention, safety easy to operate are not necessarily to special equipment, can be to avoid hypertoxic material is used, and reaction condition is mild, and moxifloxacin hydrochloride I obtained purity is high, production cost is low, is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation methods of moxifloxacin hydrochloride and its intermediate.
Background technique
Moxifloxacin hydrochloride (Moxifloxacin Hydrochloride, I), is wide spectrum and the 8- first with antibacterial activity
Oxygroup fluoroquinolone antibacterial agent, indication are to treat respiratory tract and lower respiratory tract infection, such as: acute sinusitis, chronic bronchial
Scorching acute attack, community acquired pneumonia and Skin and soft tissue infection.
Moxifloxacin shows that, to gram positive bacteria, gram-negative bacteria, anaerobic bacteria, acid fast bacteria and atypia are micro- in vitro
Biology such as mycoplasma, Chlamydia and Legionella have broad spectrum antibiotic activity.Antibacterial action mechanism is II, IV topoisomerase of interference.
Topoisomerase is control DNA topology and the key enzyme in DNA replication dna, reparation and transcription.Its killing curve shows Mo Xisha
Star is the bactericidal activity with concentration dependent.Minimum bactericidal concentration and minimum inhibitory concentration are almost the same.Moxifloxacin is to β-
Lactams and the drug resistant bacterium of macrolide antibiotics are also effective.It is confirmed by the experimental animal model of infection, Mo Xisha
Star activity in vivo is high.
The moxifloxacin hydrochloride synthetic method for having disclosed report under the conditions of the prior art has patent document
The report such as WO2008059521.
The method of patent document WO2008059521 report are as follows: the fluoro- 1,4- dihydro -8- methoxyl group-of 1- cyclopropyl -6,7- two
4- oxo -3- quinoline carboxylic acid is initially formed amide, then right with the progress condensation reaction of (S, S) -2,8- diazabicyclo [4,3,0] nonane
Hydrolysis obtains Moxifloxacin afterwards, and amide and diaza-bicyclo condensation step yield are only 46%, four step gross production rates only 29%；And acyl
Aqueous amine solution reaction condition is violent, and impurity is more and yield is not high:
The method of patent document EP550903 report are as follows: the fluoro- 1,4- dihydro -8- methoxyl group -4- oxygen of 1- cyclopropyl -6,7- two
Generation -3- quinoline carboxylic acid directly carries out condensation reaction with (S, S) -2,8- diazabicyclo [4,3,0] nonane and then purifies at salt
To Moxifloxacin, carboxylic acid and diaza-bicyclo reaction yield are only 29.5%, two step gross production rates only 22%；
The method of patent document EP0464823 report are as follows: the fluoro- 1,4- dihydro -8- methoxyl group -4- of 1- cyclopropyl -6,7- two
Oxo -3- quinoline carboxylic acid first forms boron derivative with triacetyl borine, then with (S, S) -2,8- diazabicyclo [4,3,0] nonyl
Alkane carries out condensation reaction, and then hydrolysis obtains Moxifloxacin, and boron derivative and diaza-bicyclo condensation step yield are 71% or so,
Four step gross production rates are about 40%；Triacetyl borine belongs to the explosive chemical reagent of severe toxicity, and big using harmfulness, domestic market does not have yet
There is supply, therefore be difficult to be applied to bulk pharmaceutical chemicals industrialized production:
In route made above, in addition to Article 3 preparation route because it is domestic not needed for the explosive chemical reagent supply of severe toxicity
And other than can not carrying out, the yield of committed step is not high (29%~46%), leads to total digit rate low (22%~29%), production
Cost is big, and reaction generates more impurity, and product quality is difficult to control (maximum contaminant 0.50%).So there is an urgent need to change
Prior art condition needs to find a preparation method simple to operate, to carry out the preparation of moxifloxacin hydrochloride, improves
The yield of committed step, while obtaining meeting the product of bulk pharmaceutical chemicals standard (purity is greater than 99.0%, and single contaminant is less than
0.10%), without using the reagent of severe toxicity, safe operation, and the needs of industrialized production are adapted to.
Summary of the invention
The technical problem to be solved by the present invention is in order to overcome the preparation method of moxifloxacin hydrochloride in the prior art to receive
Rate is low, product purity obtained is poor, high production cost, is not suitable for the defects of industrialized production and provides a kind of hydrochloric acid Moses
The preparation method of husky star and its intermediate.Preparation method of the invention, safety easy to operate are not necessarily to special equipment, can be to avoid
Using hypertoxic material, reaction condition is mild, moxifloxacin hydrochloride intermediate III obtained (purity is greater than 98%) with high purity, receives
Rate height (74%~79%)；And the hydrochloric acid Moses being further prepared by moxifloxacin hydrochloride intermediate III of the invention
The quality of husky star I can reach bulk pharmaceutical chemicals requirement, and (purity is greater than 99.5%, and for single contaminant less than 0.10%), total recovery is high
(50%~57%), production cost are low, are suitable for industrialized production.
The present invention provides the preparation methods of moxifloxacin hydrochloride intermediate III a kind of comprising following steps: organic
In solvent, in the presence of alkali, moxifloxacin hydrochloride intermediate II and (S, S) -2,8- diazabicyclo [4,3,0] nonane are carried out
Condensation reaction obtains moxifloxacin hydrochloride intermediate III；
The preparation method of the moxifloxacin hydrochloride intermediate III can using in this field such condensation reaction it is normal
Rule method, particularly preferably following reaction method and condition in the present invention:
In the preparation method of the moxifloxacin hydrochloride intermediate III, the preferred nitrile solvents of the organic solvent,
One of amide solvent and sulfoxide type solvents are a variety of.The preferred acetonitrile of the nitrile solvents.The amide solvent
It is preferred that N,N-dimethylformamide.The preferred dimethyl sulfoxide of the sulfoxide type solvents.
In the preparation method of the moxifloxacin hydrochloride intermediate III, the organic solvent and the hydrochloric acid
Mass volume ratio value preferred 1mL/g~30mL/g, the further preferred 2mL/g~15mL/g of moxifloxacin intermediate II, such as
7mL/g, 10mL/g or 5mL/g.
In the preparation method of the moxifloxacin hydrochloride intermediate III, the preferred organic base of the alkali or inorganic base.
One of the preferred potassium carbonate of the inorganic base, sodium carbonate and cesium carbonate are a variety of.The preferred 1,8- diazabicyclo of organic base
One of [5.4.0] 11 carbon -7- alkene, triethylene diamine, diisopropyl ethyl amine and triethylamine are a variety of, further preferably
11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0] and/or triethylene diamine.
In the preparation method of the moxifloxacin hydrochloride intermediate III, the alkali and the moxifloxacin hydrochloride
The molar ratio of star intermediate II preferably 1~5, further preferred 1.1~3.0, such as 1.8,2.5 or 1.5.
In the preparation method of the moxifloxacin hydrochloride intermediate III, (S, S) -2,8- diazabicyclo
The molar ratio preferably 1~3, further preferred 1.1~2.0 of [4,3,0] nonane and the moxifloxacin hydrochloride intermediate II,
Such as 1.5,2.0 or 1.25.
In the preparation method of the moxifloxacin hydrochloride intermediate III, the temperature of the condensation reaction preferably 60
DEG C~140 DEG C, further preferred 65 DEG C~125 DEG C such as 70 DEG C~80 DEG C, 90 DEG C~100 DEG C or 110 DEG C~120 DEG C.
In the preparation method of the moxifloxacin hydrochloride intermediate III, the process of the condensation reaction can be adopted
It is monitored with the routine monitoring method (such as TLC, HPLC or NMR) in this field, generally with the moxifloxacin hydrochloride
It is the terminal of reaction (such as TLC monitors content and is lower than 1%) when intermediate II almost disappears, the time of the condensation reaction is excellent
Select 1 hour~24 hours, further preferred 6 hours~18 hours, such as 16 hours~18 hours, 12 hours~14 hours or 8
Hour~10 hours.
The preparation method of the moxifloxacin hydrochloride intermediate III preferably carries out under protective gas protection, described
The preferred nitrogen of protective gas and/or argon gas.
The preparation method of the moxifloxacin hydrochloride intermediate III, it is preferred to use following steps: to organic solvent, salt
Alkali is added in the mixture of sour moxifloxacin intermediate II and (S, S) -2,8- diazabicyclo [4,3,0] nonane, is condensed
Reaction obtains the moxifloxacin hydrochloride intermediate III.
The preparation method of the moxifloxacin hydrochloride intermediate III, it is preferred to use following post-processing step: reaction terminates
Afterwards, cooling, moxifloxacin hydrochloride intermediate III crude product is obtained by filtration in stirring.The moxifloxacin hydrochloride intermediate III is thick
Product are preferably recrystallized to give moxifloxacin hydrochloride III.
The recrystallization preferably uses following steps: by moxifloxacin hydrochloride intermediate III crude product and organic solvent shape
At solution, cooling crystallization obtains moxifloxacin hydrochloride intermediate III.The preferred esters solvent of the organic solvent, it is described
Esters solvent ethyl acetate." solution that moxifloxacin hydrochloride intermediate III crude product and organic solvent are formed "
Preferably 60 DEG C~90 DEG C of temperature, further preferred 70 DEG C~80 DEG C.Preferably 0 DEG C~15 DEG C of the temperature of the cooling crystallization, into
Preferably 5 DEG C~10 DEG C of one step, the time of the cooling crystallization preferably 1 hour~5 hours, further preferred 2 hours~3 is small
When.
In the present invention, the preparation method of the moxifloxacin hydrochloride intermediate III preferably further includes hydrochloric acid Moses
The preparation method of husky star intermediate II comprising following steps: in organic solvent, by 2-amino-2-methyl-1-propanol and 1-
The fluoro- Isosorbide-5-Nitrae of cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid carries out condensation reaction, obtains the salt
Sour moxifloxacin intermediate II；
The preparation method of the moxifloxacin hydrochloride intermediate II can using in this field such condensation reaction it is normal
Rule method, particularly preferably following reaction method and condition in the present invention:
In the preparation method of the moxifloxacin hydrochloride intermediate II, the organic solvent preferred aromatic hydrocarbons class is molten
Agent, one of the preferred toluene of the aromatic hydrocarbon solvent, benzene and ethylbenzene or a variety of.
In the preparation method of the moxifloxacin hydrochloride intermediate II, the organic solvent and the 1- cyclopropyl
Preferred 1mL/g~the 30mL/ of volume mass ratio of the fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of base -6,7- two
G, further preferred 7mL/g~20mL/g, such as 10mL/g, 15mL/g or 7.5mL/g.
In the preparation method of the moxifloxacin hydrochloride intermediate II, the 2-amino-2-methyl-1-propanol with
The molar ratio preferably 1 of the fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of 1- cyclopropyl -6,7- two~
8, further preferred 2~5, such as 2.6,4.0 or 1.8.
In the preparation method of the moxifloxacin hydrochloride intermediate II, preferably 70 DEG C of the setting-up point~
150 DEG C, further preferred 75 DEG C~145 DEG C, such as 105 DEG C~115 DEG C, 75 DEG C~85 DEG C or 130 DEG C~140 DEG C.
In the preparation method of the moxifloxacin hydrochloride intermediate II, the process of the condensation reaction can be used
Routine monitoring method (such as TLC, HPLC or NMR) in this field is monitored, generally with the 1- cyclopropyl -6,7- bis-
When fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid almost disappears for the terminal of reaction (such as TLC monitor content
Lower than 1%), the time of the condensation reaction preferably 1 hour~24 hours, further preferred 2 hours~15 hours, such as 6
Hour~7 hours, 12 hours~14 hours or 3 hours~4 hours.
The preparation method of the moxifloxacin hydrochloride intermediate II preferably carries out under protective gas protection, the guarantor
Protect the preferred nitrogen of gas and/or argon gas.
The preparation method of the moxifloxacin hydrochloride intermediate II preferably uses following post-processing step: reaction terminates
Afterwards, cooling, washing removes solvent, mashing, filters, being dried to obtain the moxifloxacin hydrochloride intermediate II.
Preferably 10 DEG C~20 DEG C of the temperature of the cooling.The washing removes solvent, mashing, filtering, vacuum drying
It can be using the conventional method of the generic operation in this field.The washing preferably successively uses aqueous acetic acid, sodium carbonate
Solution, sodium bicarbonate aqueous solution and saline solution are washed.The mass concentration of the aqueous acetic acid preferably 1%~10%,
Such as 2%, the mass concentration refers to that the quality of acetic acid accounts for the percentage of aqueous acetic acid gross mass.The sodium carbonate
The mass concentration of solution preferably 1%~10%, such as 5%, the mass concentration refers to that the quality of sodium carbonate accounts for sodium carbonate
The percentage of solution gross mass.The mass concentration of the sodium bicarbonate aqueous solution preferably 1%~10%, such as 7%, it is described
Mass concentration refers to that the quality of sodium bicarbonate accounts for the percentage of sodium bicarbonate aqueous solution gross mass.The matter of the common salt aqueous solution
Concentration preferably 5%~25%, such as 10% are measured, the mass concentration refers to that the quality of sodium chloride accounts for common salt aqueous solution gross mass
Percentage.The removing solvent is preferably concentrated in vacuo；Preferably 35 DEG C~75 DEG C of the temperature of the vacuum concentration, such as 45
DEG C~65 DEG C, the pressure of the vacuum concentration preferably -0.08MPa~-0.1MPa.The organic solvent that the mashing uses is preferred
Alkane solvents；The preferred normal heptane of the alkane solvents.Preferably 10 DEG C~20 DEG C of the temperature of the mashing.Described beats
The time of slurry preferably 2 hours~3 hours.The drying is preferably dried in vacuo；Preferably 45 DEG C of the vacuum drying temperature
~55 DEG C；The vacuum drying time preferably 14 hours~18 hours；The vacuum drying pressure preferably-
0.01MPa~-0.1MPa.
In the present invention, the preparation method of the moxifloxacin intermediate III, it is preferred to use following route:
The present invention also provides the preparation methods of moxifloxacin hydrochloride I comprising following steps: according to the preparation side
Legal system obtains moxifloxacin intermediate III and then in organic solvent, moxifloxacin intermediate III and hydrogen chloride is carried out anti-
It answers, obtains moxifloxacin hydrochloride I；
The preparation method of the moxifloxacin hydrochloride I can be using the conventional method of such reaction in this field, this hair
Particularly preferred following reaction method and condition in bright:
In the preparation method of the moxifloxacin hydrochloride I, the preferred alcohols solvent of the organic solvent, the alcohol
One of the preferred methanol of class solvent, ethyl alcohol and isopropanol are a variety of.
In the preparation method of the moxifloxacin hydrochloride I, the alcohols solvent and the moxifloxacin hydrochloride
Volume mass ratio preferred 1mL/g~20mL/g, further preferred 2mL/g~10mL/g, such as the 3.75mL/ of intermediate III
G, 1.9mL/g or 5mL/g.
In the preparation method of the moxifloxacin hydrochloride I, the hydrogen chloride can be with hydrogen chloride gas or chlorination
The form of hydrogen solution uses, when in the form of hydrogen chloride solution in use, the preferred 1.0mol/ of the concentration of the hydrogen chloride solution
L~3mol/L, such as 2mol/L.The preferred alcohols solvent of solvent that the hydrogen chloride solution uses, the alcohols solvent are excellent
Select one of methanol, ethyl alcohol and isopropanol or a variety of.Methanol solution, the hydrogen chloride of the preferred hydrogen chloride of the hydrogen chloride solution
Ethanol solution or hydrogen chloride aqueous isopropanol.
In the preparation method of the moxifloxacin hydrochloride I, in the hydrogen chloride and the moxifloxacin hydrochloride
The molar ratio of mesosome III preferably 1~5, further preferred 2.1~4.5, such as 2.8,3.4 or 4.5.
In the preparation method of the moxifloxacin hydrochloride I, preferably 0 DEG C~60 DEG C of the reaction temperature, further
It is preferred that 20 DEG C~50 DEG C, such as 30 DEG C~40 DEG C, 20 DEG C~30 DEG C or 40 DEG C~50 DEG C.
In the preparation method of the moxifloxacin hydrochloride I, the time of the reaction preferably 1 hour~10 hours,
Further preferred 2 hours~8 hours, such as 4 hours~6 hours, 6 hours~8 hours or 3 hours~4 hours.
The preparation method of the moxifloxacin hydrochloride I preferably carries out under protective gas protection, the protective gas
It is preferred that nitrogen and/or argon gas.
The preparation method of the moxifloxacin hydrochloride I preferably uses following steps: by moxifloxacin hydrochloride intermediate III
It is added in the mixture of organic solvent and hydrogen chloride, is reacted to obtain moxifloxacin hydrochloride I.
The preparation method of the moxifloxacin hydrochloride I preferably uses following post-processing step: after reaction, removing molten
Agent, cooling are beaten, and washing is dried to obtain moxifloxacin hydrochloride I crude product.
The removing solvent, cooling are beaten, washing, and drying can be using the conventional method of the generic operation in this field.
The removing solvent is preferably using vacuum concentration.Preferably 35 DEG C~55 DEG C of the temperature of the vacuum concentration, such as 35 DEG C~
45℃.The pressure of the vacuum concentration preferably -0.08MPa~-0.1MPa.The cooling is preferably cooled to 0 DEG C~30 DEG C,
Such as 20 DEG C~25 DEG C or 10 DEG C~15 DEG C.The preferred halogenated hydrocarbon solvent of solvent that the mashing uses；The halogenated hydrocarbons
The preferred chlorinated hydrocarbon solvent of class solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.The solvent that the washing uses is excellent
Select halogenated hydrocarbon solvent；The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, the preferred dichloro of the chlorinated hydrocarbon solvent
Methane.The drying is preferably dried in vacuo；Preferably 45 DEG C~55 DEG C of the vacuum drying temperature；The vacuum drying
Time preferably 8 hours~12 hours；The vacuum drying pressure preferably -0.01MPa~-0.1MPa.
Moxifloxacin hydrochloride I crude product is preferably through being recrystallized to give moxifloxacin hydrochloride I crude product.What the recrystallization used
The mixed solvent of organic solvent preferred alcohols solvent and halogenated hydrocarbon solvent.The preferred methanol of the alcohols solvent.The halogen
For the preferred chlorinated hydrocarbon solvent of hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent." alcohols solvent and the halogen
For the mixed solvent of hydrocarbon solvent " preferably methanol and methylene chloride mixed solvent.It is described that " alcohols solvent is molten with halogenated hydrocarbon
The volume ratio preferably 1~5 of alcohols solvent described in the mixed solvent of agent " and the halogenated hydrocarbon solvent, such as 2.5.
The recrystallization preferably uses following steps: the solution that moxifloxacin hydrochloride I crude product and alcohols solvent are formed
It is mixed again with halogenated hydrocarbon solvent, cooling crystallization obtains moxifloxacin hydrochloride I." moxifloxacin hydrochloride I crude product and the alcohols
Preferably 40 DEG C~45 DEG C of temperature of the solution that solvent is formed ".Preferably 0~5 DEG C of the temperature of the cooling crystallization.The cooling
The time of crystallization preferably 1 hour~5 hours, such as 3 hours~4 hours.
In the present invention, the preparation method of the moxifloxacin hydrochloride I, it is preferred to use following route:
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
In the present invention, the room temperature refers to environment temperature, is 10 DEG C~35 DEG C.
The positive effect of the present invention is that: preparation method of the invention, it is easy to operate safety, be not necessarily to special equipment,
Can be to avoid hypertoxic material be used, reaction condition is mild, and (purity is greater than moxifloxacin hydrochloride intermediate III purity is high obtained
98%), high income (74%~79%)；And it is further prepared by moxifloxacin hydrochloride intermediate III of the invention
The quality of moxifloxacin hydrochloride I can reach bulk pharmaceutical chemicals requirement, and (purity is greater than 99.5%, and single contaminant is always received less than 0.10%)
Rate height (50%~57%), production cost are low, are suitable for industrialized production.
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Specific embodiment
Embodiment 1: the preparation of moxifloxacin hydrochloride intermediate II
Under nitrogen protection, the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxygen is added into toluene 100L
Generation -3- quinoline carboxylic acid 10.0Kg (33.87mol) and 2-amino-2-methyl-1-propanol 7.95Kg (89.19mol), are heated to 105
~115 DEG C of water for flowing back 6~7 hours and separating generation, until reaching the amount of metering or not being further added by.It is cooled to 10 DEG C~20
DEG C, being sequentially added into mass concentration is that (it is water-soluble that the mass concentration refers to that the quality of acetic acid accounts for acetic acid to 2% aqueous acetic acid
The percentage of liquid gross mass), mass concentration be 5% aqueous sodium carbonate (mass concentration refers to that the quality of sodium carbonate accounts for
The percentage of aqueous sodium carbonate gross mass), mass concentration be 7% sodium bicarbonate aqueous solution (mass concentration refers to carbon
The quality of sour hydrogen sodium accounts for the percentage of sodium bicarbonate aqueous solution gross mass), mass concentration be 10% saline solution (quality is dense
Degree refers to that the quality of sodium chloride accounts for the percentage of saline solution gross mass) it stirs afterwards, stand, separate water layer.Organic layer in vacuo concentration
(temperature 45 C~65 DEG C, pressure -0.08MPa~-0.1MPa) removes most of solvent, and normal heptane 70L is added, it is cooled to 10~
20 DEG C are stirred 2~3 hours.Centrifugation three times with normal heptane elution is dried in vacuo (vacuum degree -0.01MPa~-0.1MPa, temperature
45~55 DEG C) it is 14~18 hours dry, obtain 11.4kg moxifloxacin hydrochloride intermediate II, yield 96.6%.HPLC purity
96.38%.
Embodiment 2: the preparation of moxifloxacin hydrochloride intermediate II
Under nitrogen protection, the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxo-is added into benzene 750mL
3- quinoline carboxylic acid 50.0g (0.169mol) and 2-amino-2-methyl-1-propanol 60.4g (0.678mol), is heated to 75~85 DEG C
Flow back 12~14 hours and separate the water of generation.10 DEG C~20 DEG C are cooled to, being sequentially added into mass concentration is 2% acetic acid water
Solution (mass concentration refers to that the quality of acetic acid accounts for the percentage of aqueous acetic acid gross mass), mass concentration are 5% carbon
Acid sodium aqueous solution (mass concentration refers to that the quality of sodium carbonate accounts for the percentage of aqueous sodium carbonate gross mass), quality are dense
Degree is that (mass concentration refers to that the quality of sodium bicarbonate accounts for sodium bicarbonate aqueous solution gross mass to 7% sodium bicarbonate aqueous solution
Percentage), mass concentration be 10% saline solution (mass concentration refers to that the quality of sodium chloride accounts for saline solution gross mass
Percentage) it stirs afterwards, stand, separate water layer.Organic layer in vacuo concentration (35 DEG C~55 DEG C of temperature, pressure -0.08MPa~-
Most of solvent 0.1MPa) is removed, normal heptane 350mL is added, 10~20 DEG C is cooled to and stirs 2~3 hours.Centrifugation, with positive heptan
Alkane elutes three times, and vacuum drying (vacuum degree -0.01MPa~-0.1MPa, 45~55 DEG C of temperature) is 14 hours~18 hours dry,
Obtain 56.4g moxifloxacin hydrochloride intermediate II, yield 95.6%.HPLC purity 96.24%.
Embodiment 3: the preparation of moxifloxacin hydrochloride intermediate II
Under nitrogen protection, the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxygen is added into ethylbenzene 150mL
Generation -3- quinoline carboxylic acid 20.0g (0.0677mol) and 2-amino-2-methyl-1-propanol 10.9g (0.122mol), are heated to 130
DEG C~140 DEG C of water for flowing back 3 hours~4 hours and separating generation.10 DEG C~20 DEG C are cooled to, mass concentration is sequentially added into
For 2% aqueous acetic acid (mass concentration refers to that the quality of acetic acid accounts for the percentage of aqueous acetic acid gross mass), quality
Concentration is that (mass concentration refers to that the quality of sodium carbonate accounts for the hundred of aqueous sodium carbonate gross mass to 5% aqueous sodium carbonate
Point ratio), (mass concentration refers to that the quality of sodium bicarbonate accounts for sodium bicarbonate to mass concentration for 7% sodium bicarbonate aqueous solution
The percentage of aqueous solution gross mass), mass concentration be 10% saline solution (mass concentration refers to that the quality of sodium chloride accounts for food
The percentage of salt water gross mass) it stirs afterwards, stand, separate water layer.Organic layer in vacuo concentration (55 DEG C~75 DEG C of temperature, pressure-
0.08MPa~-0.1MPa) most of solvent is removed, normal heptane 350mL is added, is cooled to 10~20 DEG C and stirs 2~3 hours.From
The heart, three times with normal heptane elution, vacuum drying (vacuum degree -0.01MPa~-0.1MPa, 45~55 DEG C of temperature) dry 14~18
Hour, obtain 22.5g moxifloxacin hydrochloride intermediate II, yield 95.4%.HPLC purity 95.67%.
Embodiment 4: the preparation of moxifloxacin hydrochloride intermediate III
Under nitrogen protection, into acetonitrile 70L, (28.7mol, HPLC are pure by addition moxifloxacin hydrochloride intermediate II 10.0Kg
96.38%) degree with (S, S) -2,8- diazabicyclo [4,3,0] nonane 5.44Kg (43.1mol), stirs at 20 DEG C~30 DEG C
And 1,8- diazabicyclo [5.4.0] 11 carbon -7- alkene 7.87Kg (51.7mol) is added, it is small that 16 are stirred at 70 DEG C~80 DEG C
When~18 hours.It progressively cools to and is stirred 2 hours~3 hours at 5 DEG C~10 DEG C.Centrifugation, is eluted and is drained with acetonitrile.Nitrogen is protected
Under shield, batch wet product entirely is added to ethyl acetate 60L, is stirred 1 hour~2 hours at 70 DEG C~80 DEG C, progressively cool to 5 DEG C~
It is stirred 2 hours~3 hours at 10 DEG C.Centrifugation, is eluted and is drained with ethyl acetate.Vacuum drying (vacuum degree -0.01MPa~-
0.1MPa, temperature 45 C~55 DEG C) it is 16 hours dry, obtain 10.2Kg moxifloxacin hydrochloride intermediate III, yield 78.2%.
HPLC purity 98.84%.
Embodiment 5: the preparation of moxifloxacin hydrochloride intermediate III
Under nitrogen protection, moxifloxacin hydrochloride intermediate II 50.0g is added into n,N-Dimethylformamide 500mL
(0.144mol, HPLC purity 96.24%) and (S, S) -2,8- diazabicyclo [4,3,0] nonane 36.3g (0.288mol),
It stirs and is added potassium carbonate 49.7g (0.360mol) at 20 DEG C~30 DEG C, it is small that 12 hours~14 are stirred at 90 DEG C~100 DEG C
When.It progressively cools at 5 DEG C~10 DEG C, and water 1000mL is added, be stirred for 2 hours~3 hours.Filtering, is eluted and is taken out with water
It is dry.Under nitrogen protection, batch wet product entirely is added to ethyl acetate 300mL, stirs 1 hour~2 hours at 70 DEG C~80 DEG C, slowly
It is cooled at 5 DEG C~10 DEG C and stirs 2 hours~3 hours.Filtering, is eluted and is drained with ethyl acetate.It is dried in vacuo (vacuum degree-
0.01MPa~-0.1MPa, temperature 45 C~55 DEG C) it is 16 hours dry, 49.8g moxifloxacin hydrochloride intermediate III is obtained, is received
Rate 76.3%.HPLC purity 98.52%.
Embodiment 6: the preparation of moxifloxacin hydrochloride intermediate III
Under nitrogen protection, into dimethyl sulfoxide 100mL be added moxifloxacin hydrochloride intermediate II 20.0g (0.0574mol,
HPLC purity 95.67%) and (S, S) -2,8- diazabicyclo [4,3,0] nonane 9.06g (0.0718mol), 20 DEG C~30
It stirs and is added triethylene diamine 9.65g (0.0860mol) at DEG C, stirred 8 hours~10 hours at 110 DEG C~120 DEG C.It is slow
Water 400mL is added at 5 DEG C~10 DEG C in slow cool down, is stirred for 2 hours~3 hours.Filtering, is eluted and is drained with water.Nitrogen
Under protection, batch wet product entirely is added to ethyl acetate 120mL, is stirred 1 hour~2 hours at 70 DEG C~80 DEG C, progressively cools to 5
DEG C~10 DEG C at stir 2 hours~3 hours.Filtering, is eluted and is drained with ethyl acetate.It is dried in vacuo (vacuum degree -0.01MPa
~-0.1MPa, temperature 45 C~55 DEG C) it is 16 hours dry, obtain 19.3g moxifloxacin hydrochloride intermediate III, yield
74.0%.HPLC purity 98.16%.
Embodiment 7: the preparation of moxifloxacin hydrochloride I
Under nitrogen protection, under stirring to ethyl alcohol 30L and 2.0mol/L ethanol solution of hydrogen chloride 30L (60mol) mixing
Moxifloxacin hydrochloride intermediate III 8.00Kg (17.6mol) is added in liquid, stirs 4 hours~6 at 30 DEG C~40 DEG C after addition
Hour.The most of solvent of (35 DEG C~55 DEG C of temperature, pressure -0.08MPa~-0.1MPa) removals of vacuum concentration, is cooled to 10 DEG C
~15 DEG C, methylene chloride 40L is added, is stirred 1 hour~2 hours at 0~5 DEG C.Filtering, is washed, wet product exists with methylene chloride 10L
It is 8 hours~12 hours dry in 45 DEG C~55 DEG C of drying box of vacuum (pressure -0.01MPa~-0.1MPa), obtain yellow solid salt
Sour Moxifloxacin I crude product 7.71Kg, yield 100%, HPLC purity 99.32%.Under nitrogen protection, put into methanol 38L complete
Moxifloxacin hydrochloride I crude product is criticized, be heated to 40 DEG C~45 DEG C and is stirred 1 hour~2 hours.Methylene chloride 15L is added, and cooling
It is stirred 3 hours~4 hours to 0~5 DEG C.Filtering, washed with methylene chloride 10L, wet product vacuum (pressure -0.01MPa~-
It is 0.1MPa) 8 hours~12 hours dry in 45 DEG C~55 DEG C of drying box, 5.78Kg light yellow solid moxifloxacin hydrochloride I is obtained,
(the total recovery 56.7%, with the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic of yield 75.0%
Acid meter).HPLC purity 99.87%, maximum single contaminant 0.04%.
Embodiment 8: the preparation of moxifloxacin hydrochloride I
Under nitrogen protection, to the hydrogen chloride methanol solution 140mL (0.28mol) of methanol 85mL and 2.0mol/L under stirring
Moxifloxacin hydrochloride intermediate III 45.0g (0.0990mol) is added in mixed liquor, it is small in 20 DEG C~30 DEG C stirrings 6 after addition
When~8 hours.The most of solvent of (35 DEG C~45 DEG C of temperature, pressure -0.08MPa~-0.1MPa) removals of vacuum concentration, is cooled to
10 DEG C~15 DEG C, methylene chloride 225mL is added, is stirred 1 hour~2 hours at 0~5 DEG C.Filtering, is washed with methylene chloride 60mL
It washs, wet product is 8 hours~12 hours dry in 45 DEG C~55 DEG C of drying box of vacuum (pressure -0.01MPa~-0.1MPa), obtains
Yellow solid moxifloxacin hydrochloride I crude product 43.2g, yield 99.7%, HPLC purity 99.17%.Under nitrogen protection, to methanol
Batch moxifloxacin hydrochloride I crude product entirely is put into 213mL, is heated to 40 DEG C~45 DEG C and is stirred 1 hour~2 hours.Dichloro is added
Methane 84mL, and be cooled to 0~5 DEG C and stir 3 hours~4 hours.Filtering, is washed, wet product is in vacuum (pressure-with methylene chloride
0.01MPa~-0.1MPa) it is 8 hours~12 hours dry in 45 DEG C~55 DEG C of drying box, obtain light yellow solid moxifloxacin hydrochloride
Star the I32.3g, (total recovery 54.6%, with the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxygen of yield 74.8%
In generation, -3- quinoline carboxylic acid counted).HPLC purity 99.84%, maximum single contaminant 0.05%.
Embodiment 9: the preparation of moxifloxacin hydrochloride I
Under nitrogen protection, to the isopropanol solution of hydrogen chloride 90mL of isopropanol 90mL and 2.0mol/L under stirring
In the mixed liquor of (0.18mol) be added moxifloxacin hydrochloride intermediate III 18.0g (0.0396mol), after addition 40 DEG C~
50 DEG C are stirred 3 hours~4 hours.It is most of to be concentrated in vacuo (temperature 45 C~55 DEG C, pressure -0.08MPa~-0.1MPa) removal
Solvent is cooled to 10 DEG C~15 DEG C, and methylene chloride 90mL is added, and stirs 1 hour~2 hours at 0~5 DEG C.Filtering, uses dichloromethane
Alkane 24mL washing, wet product are dry 8 hours~12 small in 45 DEG C~55 DEG C of drying box of vacuum (pressure -0.01MPa~-0.1MPa)
When, obtain yellow solid moxifloxacin hydrochloride I crude product 17.2g, yield 99.2%, HPLC purity 99.17%.Under nitrogen protection,
Batch moxifloxacin hydrochloride I crude product entirely is put into methanol 86mL, is heated to 40 DEG C~45 DEG C and is stirred 1 hour~2 hours.It is added
Methylene chloride 34mL, and be cooled to 0~5 DEG C and stir 3 hours~4 hours.Filtering, is washed with methylene chloride, and wet product is in vacuum (pressure
- 0.01MPa~-0.1MPa by force) it is 8 hours~12 hours dry in 45 DEG C~55 DEG C of drying box, obtain 12.4g light yellow solid salt
Sour Moxifloxacin the I, (total recovery 50.9%, with the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- of yield 72.1%
Oxo -3- quinoline carboxylic acid meter).HPLC purity 99.79%, maximum single contaminant 0.05%.
Comparative example 1: the preparation of moxifloxacin hydrochloride I (according to the method for patent WO2008059521)
Under nitrogen protection, into n,N-Dimethylformamide 150mL, the fluoro- Isosorbide-5-Nitrae-two of 1- cyclopropyl -6,7- bis- is sequentially added
Hydrogen -8- methoxyl group -4- oxo -3- quinoline carboxylic acid 25.0g (0.0847mol), diethylamine hydrochloride 14.0g (0.128mol), 1-
Hydroxybenzotriazole 20.0g (0.148mol), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride 28.4g
(0.148mol), diisopropyl ethyl amine 57.4g (0.445mol), is then stirred at room temperature 2~3 hours, and water is added, uses acetic acid
Ethyl ester is extracted twice.Merging organic phase to be sequentially added into mass concentration is that (mass concentration refers to 5% aqueous hydrochloric acid solution
The quality of acetic acid accounts for the percentage of aqueous acetic acid gross mass), mass concentration be the 7% sodium bicarbonate aqueous solution (quality
Concentration refers to that the quality of sodium bicarbonate accounts for the percentage of sodium bicarbonate aqueous solution gross mass), mass concentration be 10% saline solution (institute
The mass concentration stated refers to that the quality of sodium chloride accounts for the percentage of saline solution gross mass) it stirs afterwards, stand, separate water layer.It is organic
Layer is concentrated in vacuo the most of solvent of (35 DEG C~55 DEG C of temperature, pressure -0.08MPa~-0.1MPa) removals, and normal heptane is added, cold
But it to 10~20 DEG C of stirrings, filtering, is eluted with normal heptane, vacuum drying (vacuum degree -0.01MPa~-0.1MPa, temperature 45~
55 DEG C) 16 hours, obtain the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid's diformamide
25.9g, yield 87.3%.HPLC purity 95.67%.
Under nitrogen protection, the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxygen is added into acetonitrile 100mL
Generation -3- quinoline carboxylic acid diformamide 20.0g (0.0571mol) and (S, S) -2,8- diazabicyclo [4,3,0] nonane 11.8g
(0.0935mol) is stirred at 20 DEG C~30 DEG C and 1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene 12.5g is added
(0.0821mol) is stirred 35 hours at 75 DEG C~85 DEG C.It progressively cools to and is stirred 2 hours~3 hours at 5 DEG C~10 DEG C.It crosses
Filter, is eluted and is drained with acetonitrile.It is dried in vacuo (vacuum degree -0.01MPa~-0.1MPa, temperature 45 C~55 DEG C) 16 hours, obtains
To 7- ((S, S) -2,8- diazabicyclo [4,3,0] nonane -2- base) the fluoro- 1,4- dihydro -8- methoxyl group -4- of -1- cyclopropyl -6-
Oxo -3- quinoline carboxylic acid diformamide 12.0g, yield 46.0%.HPLC purity 94.69%.
Under nitrogen protection, sodium hydroxide 35g (0.875mol) and 7- ((S, S)-is added to water 165mL, ethylene glycol 150mL
2,8- diazabicyclo [4,3,0] nonane -8- base) the fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline of -1- cyclopropyl -6-
Carboxylic acid diformamide 12.0g (0.0263mol) is heated to stir 15 hours at 115 DEG C.5 DEG C are cooled to, adjusts pH with concentrated hydrochloric acid
To 5~6.It stirs 0.5 hour, filters at 5 DEG C, washing is dried in vacuo (vacuum degree -0.01MPa~-0.1MPa, temperature 45 C
~55 DEG C) 16 hours, obtain Moxifloxacin 8.0g, yield 75.8%.HPLC purity 93.25%.
Under nitrogen protection, Moxifloxacin 8.0g is added into water 5mL and methanol 20mL, is heated to stir 1 hour at 70 DEG C,
Filtering is cooled to 35 DEG C, and 6N salt acid for adjusting pH is added to 1.4~1.8.15 DEG C are cooled to stir 1 hour.Filtering, washing, and
In water 10mL and concentrated hydrochloric acid 0.2mL solution, 15 DEG C are stirred 1 hour.Filtering, washing, vacuum drying (vacuum degree -0.01MPa~-
0.1MPa, 45~55 DEG C of temperature) 16 hours, obtain moxifloxacin hydrochloride the 6.4g, (total recovery 29.4%, with 1- of yield 73.3%
The fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of cyclopropyl -6,7- two meter).HPLC purity 99.16%, it is maximum single
One impurity 0.54%.
Comparative example 2: the preparation of moxifloxacin hydrochloride I (according to the method for patent EP550903)
Under nitrogen protection, the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxyl group -4- oxygen is added into acetonitrile 70mL
Generation -3- quinoline carboxylic acid 10.0g (0.0339mol) and (S, S) -2,8- diazabicyclo [4,3,0] nonane 5.13g
(0.0406mol) is stirred at 20 DEG C~30 DEG C and 1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene 7.74g is added
(0.0508mol) is stirred 36 hours at 75 DEG C~85 DEG C.Vacuum concentration (temperature 45 C~65 DEG C, pressure -0.08MPa~-
Most of solvent 0.1MPa) is removed, chloroform is then dissolved in, being sequentially added into mass concentration is that 2% aqueous acetic acid is (described
Mass concentration refers to that the quality of acetic acid accounts for the percentage of aqueous acetic acid gross mass), mass concentration be 10% saline solution it is (described
Mass concentration refers to that the quality of sodium chloride accounts for the percentage of saline solution gross mass) it stirs afterwards, stand, separate water layer.Organic layer is true
The most of solvent of (35 DEG C~55 DEG C of temperature, pressure -0.08MPa~-0.1MPa) removals is concentrated in sky, and ethyl acetate is added, cooling
It is stirred 2 hours~3 hours to 10 DEG C~20 DEG C.Centrifugation three times with ethyl acetate elution is dried in vacuo (vacuum degree -0.01MPa
~-0.1MPa, 45~55 DEG C of temperature) it is 14~18 hours dry, obtain Moxifloxacin 4.01g, yield 29.5%.HPLC purity
93.54%.
Under nitrogen protection, Moxifloxacin 4.0g is added into water 2.5mL and methanol 10mL, it is small to be heated to stirring 1 at 70 DEG C
When, filtering is cooled to 35 DEG C, and 6N salt acid for adjusting pH is added to 1.4~1.8.15 DEG C are cooled to stir 1 hour.Filtering, washing,
And in water 5mL and concentrated hydrochloric acid 0.2mL solution, 15 DEG C are stirred 1 hour.Filtering, washing are dried in vacuo (vacuum degree -0.01MPa
~-0.1MPa, 45~55 DEG C of temperature) 16 hours, obtain moxifloxacin hydrochloride 3.3g, yield 75.6% (total recovery 22.3%, with
The fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of 1- cyclopropyl -6,7- two meter).HPLC purity 99.23%, it is maximum
Single contaminant 0.47%.
Claims (10)
1. a kind of preparation method of moxifloxacin hydrochloride intermediate III, it is characterised in that it is the following steps are included: in organic solvent
In, in the presence of alkali, moxifloxacin hydrochloride intermediate II and (S, S) -2,8- diazabicyclo [4,3,0] nonane are condensed
Reaction, obtains moxifloxacin hydrochloride intermediate III；
2. the preparation method of moxifloxacin hydrochloride intermediate III as described in claim 1, it is characterised in that:
In the preparation method of the moxifloxacin hydrochloride intermediate III, the organic solvent is nitrile solvents, amides
One of solvent and sulfoxide type solvents are a variety of；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the organic solvent and the hydrochloric acid Moses
The mass volume ratio value of husky star intermediate II is 1mL/g~30mL/g；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the alkali is organic base or inorganic base；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, in the alkali and the moxifloxacin hydrochloride
The molar ratio of mesosome II is 1~5；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, (S, S) -2,8- diazabicyclo [4,3,
0] molar ratio of nonane and the moxifloxacin hydrochloride intermediate II are 1~3；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the temperature of the condensation reaction is 60 DEG C~140
℃；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the time of the condensation reaction is 1 hour~24
Hour；
And/or
The preparation method of the moxifloxacin hydrochloride intermediate III carries out under protective gas protection；
And/or
The preparation method of the moxifloxacin hydrochloride intermediate III, using following steps: to organic solvent, moxifloxacin hydrochloride
Alkali is added in the mixture of star intermediate II and (S, S) -2,8- diazabicyclo [4,3,0] nonane, carries out condensation reaction and obtains
The moxifloxacin hydrochloride intermediate III；
And/or
The preparation method of the moxifloxacin hydrochloride intermediate III, using following post-processing step: it is after reaction, cooling,
Stirring, is obtained by filtration moxifloxacin hydrochloride intermediate III crude product.
3. the preparation method of moxifloxacin hydrochloride intermediate III as claimed in claim 2, it is characterised in that:
In the preparation method of the moxifloxacin hydrochloride intermediate III, the nitrile solvents are acetonitrile；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the amide solvent is N, N- dimethyl methyl
Amide；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the sulfoxide type solvents are dimethyl sulfoxide；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the organic solvent and the hydrochloric acid Moses
The mass volume ratio value of husky star intermediate II is 2mL/g~15mL/g；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the inorganic base is potassium carbonate, sodium carbonate and carbon
One of sour caesium is a variety of；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the organic base is 1,8- diazabicyclo
One of [5.4.0] 11 carbon -7- alkene, triethylene diamine, diisopropyl ethyl amine and triethylamine are a variety of；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, in the alkali and the moxifloxacin hydrochloride
The molar ratio of mesosome II is 1.1~3.0；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, (S, S) -2,8- diazabicyclo [4,3,
0] molar ratio of nonane and the moxifloxacin hydrochloride intermediate II are 1.1~2.0；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the temperature of the condensation reaction is 65 DEG C~125
℃；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the time of the condensation reaction is 6 hours~18
Hour；
And/or
When the preparation method of the moxifloxacin hydrochloride intermediate III carries out under protective gas protection；The protection
Gas is nitrogen and/or argon gas；
And/or
The moxifloxacin hydrochloride intermediate III crude product is recrystallized to give moxifloxacin hydrochloride III.
4. the preparation method of moxifloxacin hydrochloride intermediate III as claimed in claim 3, it is characterised in that:
In the preparation method of the moxifloxacin hydrochloride intermediate III, the organic solvent and the hydrochloric acid Moses
The mass volume ratio value of husky star intermediate II is 7mL/g, 10mL/g or 5mL/g；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, in the alkali and the moxifloxacin hydrochloride
The molar ratio of mesosome II is 1.8,2.5 or 1.5；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, (S, S) -2,8- diazabicyclo [4,3,
0] molar ratio of nonane and the moxifloxacin hydrochloride intermediate II are 1.5,2.0 or 1.25；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, the temperature of the condensation reaction is 70 DEG C~80
DEG C, 90 DEG C~100 DEG C or 110 DEG C~120 DEG C；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate III, time of the condensation reaction is 16 hours~
18 hours, 12 hours~14 hours or 8 hours~10 hours；
And/or
The recrystallization uses following steps: the solution that moxifloxacin hydrochloride intermediate III crude product and organic solvent are formed,
Cooling crystallization obtains moxifloxacin hydrochloride intermediate III.
5. the preparation method of moxifloxacin hydrochloride intermediate III as described in claim 1, it is characterised in that: the hydrochloric acid
The preparation method of moxifloxacin intermediate III further comprises the preparation method of moxifloxacin hydrochloride intermediate II comprising with
Lower step: in organic solvent, by 2-amino-2-methyl-1-propanol and the fluoro- Isosorbide-5-Nitrae of 1- cyclopropyl -6,7- bis--dihydro -8- methoxy
Base -4- oxo -3- quinoline carboxylic acid carries out condensation reaction, obtains the moxifloxacin hydrochloride intermediate II；
6. the preparation method of moxifloxacin hydrochloride intermediate III as claimed in claim 5, it is characterised in that:
In the preparation method of the moxifloxacin hydrochloride intermediate II, the organic solvent is aromatic hydrocarbon solvent；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the organic solvent and the 1- cyclopropyl-
The volume mass ratio of the fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of 6,7- bis- is 1mL/g~30mL/g；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the 2-amino-2-methyl-1-propanol with it is described
The fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of 1- cyclopropyl -6,7- two molar ratio be 1~8；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the setting-up point is 70 DEG C~150 DEG C；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the time of the condensation reaction is 1 hour~24
Hour；
And/or
The preparation method of the moxifloxacin hydrochloride intermediate II carries out under protective gas protection.
7. the preparation method of moxifloxacin hydrochloride intermediate III as claimed in claim 6, it is characterised in that:
In the preparation method of the moxifloxacin hydrochloride intermediate II, the aromatic hydrocarbon solvent is toluene, benzene and ethylbenzene
One of or it is a variety of；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the organic solvent and the 1- cyclopropyl-
The volume mass ratio of the fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of 6,7- bis- is 7mL/g~20mL/g；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the 2-amino-2-methyl-1-propanol with it is described
The fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of 1- cyclopropyl -6,7- two molar ratio be 2~5；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the setting-up point is 75 DEG C~145 DEG C；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the time of the condensation reaction is 2 hours~15
Hour；
And/or
When the preparation method of the moxifloxacin hydrochloride intermediate II carries out under protective gas protection；The protection gas
Body is nitrogen and/or argon gas.
8. the preparation method of moxifloxacin hydrochloride intermediate III as claimed in claim 7, it is characterised in that: in the salt
In the preparation method of sour moxifloxacin intermediate II, the organic solvent and the fluoro- Isosorbide-5-Nitrae-two of 1- cyclopropyl -6,7- bis-
The volume mass ratio of hydrogen -8- methoxyl group -4- oxo -3- quinoline carboxylic acid is 10mL/g, 15mL/g or 7.5mL/g；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the 2-amino-2-methyl-1-propanol with it is described
The fluoro- 1,4- dihydro -8- methoxyl group -4- oxo -3- quinoline carboxylic acid of 1- cyclopropyl -6,7- two molar ratio be 2.6,4.0 or
1.8；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the setting-up point is 105 DEG C~115
DEG C, 75 DEG C~85 DEG C or 130 DEG C~140 DEG C；
And/or
In the preparation method of the moxifloxacin hydrochloride intermediate II, the time of the condensation reaction is 6 hours~7 small
When, 12 hours~14 hours or 3 hours~4 hours.
9. a kind of preparation method of moxifloxacin hydrochloride I, it is characterised in that: preparation according to any one of claims 1 to 8
Moxifloxacin intermediate III and then in organic solvent is made in method, and moxifloxacin intermediate III and hydrogen chloride are carried out
Reaction, obtains moxifloxacin hydrochloride I；
10. the preparation method of moxifloxacin hydrochloride I as claimed in claim 9, it is characterised in that:
In the preparation method of the moxifloxacin hydrochloride I, the organic solvent is alcohols solvent；
And/or
In the preparation method of the moxifloxacin hydrochloride I, among the alcohols solvent and the moxifloxacin hydrochloride
The volume mass ratio of body III is 1mL/g~20mL/g；
And/or
In the preparation method of the moxifloxacin hydrochloride I, the hydrogen chloride is with hydrogen chloride gas or hydrogen chloride solution
Form uses；
And/or
In the preparation method of the moxifloxacin hydrochloride I, the hydrogen chloride and the moxifloxacin hydrochloride intermediate
The molar ratio of III is 1~5；
And/or
In the preparation method of the moxifloxacin hydrochloride I, the reaction temperature is 0 DEG C~60 DEG C；
And/or
In the preparation method of the moxifloxacin hydrochloride I, the time of the reaction is 1 hour~10 hours；
And/or
The preparation method of the moxifloxacin hydrochloride I carries out under protective gas protection；
And/or
The preparation method of the moxifloxacin hydrochloride I uses following steps: moxifloxacin hydrochloride intermediate III has been added to
In the mixture of solvent and hydrogen chloride, reacted to obtain moxifloxacin hydrochloride I.
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Cited By (2)
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|---|---|---|---|---|
| CN111171022A (en) * | 2020-01-02 | 2020-05-19 | 浙江工业大学 | Synthesis method of 1-hydroxy-pyrrolo [2,3-c ] piperidine |
| CN115322191A (en) * | 2022-07-25 | 2022-11-11 | 苏州汉德创宏生化科技有限公司 | Method for synthesizing moxifloxacin hydrochloride |
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Effective date of registration: 20220210 Address after: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang hi tech park, Zhangjiang hi tech park, Pudong New Area, Shanghai Patentee after: SHANGHAI BOCIMED PHARMACEUTICAL Co.,Ltd. Patentee after: Shanghai xinlitai Pharmaceutical Co.,Ltd. Address before: Room A679-04, Building No. 2, 351 GuoShoujing Road, China (Shanghai) Free Trade Pilot Area, Pudong New Area, Shanghai, 201203 Patentee before: SHANGHAI BOCIMED PHARMACEUTICAL Co.,Ltd. |
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Address after: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Patentee after: Shanghai Yunshengyan neoplasm Technology Co.,Ltd. Patentee after: Shanghai xinlitai Pharmaceutical Co.,Ltd. Address before: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai Patentee before: SHANGHAI BOCIMED PHARMACEUTICAL Co.,Ltd. Patentee before: Shanghai xinlitai Pharmaceutical Co.,Ltd. |
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Effective date of registration: 20230608 Address after: 201306 floor 3 and 4, Building 29, No. 356, ZHENGBO Road, Lingang xinpian District, China (Shanghai) pilot Free Trade Zone, Fengxian District, Shanghai Patentee after: Shanghai xinlitai Pharmaceutical Co.,Ltd. Address before: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang hi tech park, Zhangjiang hi tech park, Pudong New Area, Shanghai Patentee before: Shanghai Yunshengyan neoplasm Technology Co.,Ltd. Patentee before: Shanghai xinlitai Pharmaceutical Co.,Ltd. |
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Denomination of invention: Preparation method of moxifloxacin hydrochloride and its intermediates Effective date of registration: 20230807 Granted publication date: 20210528 Pledgee: Bank of Shanghai Limited by Share Ltd. Pudong branch Pledgor: Shanghai xinlitai Pharmaceutical Co.,Ltd. Registration number: Y2023310000446 |
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