CN104277059A - Preparation method of fluoroquinolone antibacterial drug - Google Patents
Preparation method of fluoroquinolone antibacterial drug Download PDFInfo
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- CN104277059A CN104277059A CN201410306465.XA CN201410306465A CN104277059A CN 104277059 A CN104277059 A CN 104277059A CN 201410306465 A CN201410306465 A CN 201410306465A CN 104277059 A CN104277059 A CN 104277059A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 229940124307 fluoroquinolone Drugs 0.000 title abstract description 4
- 229940124350 antibacterial drug Drugs 0.000 title abstract 2
- SKZIMSDWAIZNDD-WJMOHVQJSA-N 7-[(4as,7as)-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid;hydrate;hydrochloride Chemical compound O.Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 SKZIMSDWAIZNDD-WJMOHVQJSA-N 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- KUGSJJNCCNSRMM-UHFFFAOYSA-N ethoxyboronic acid Chemical compound CCOB(O)O KUGSJJNCCNSRMM-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 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 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 230000001476 alcoholic effect Effects 0.000 claims abstract description 6
- 239000012141 concentrate Substances 0.000 claims abstract description 4
- 239000011541 reaction mixture Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 44
- 239000000243 solution Substances 0.000 claims description 32
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 150000007530 organic bases Chemical class 0.000 claims description 16
- 150000008282 halocarbons Chemical class 0.000 claims description 14
- 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 11
- 229960003702 moxifloxacin Drugs 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 238000010009 beating Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000005406 washing Methods 0.000 abstract description 6
- 239000003513 alkali Substances 0.000 abstract description 2
- 150000005826 halohydrocarbons Chemical class 0.000 abstract description 2
- 239000013522 chelant Substances 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- -1 boron ester Chemical class 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- XPAOPAPDCRLMTR-UHFFFAOYSA-N ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxoquinoline-3-carboxylate Chemical compound C12=C(OC)C(F)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 XPAOPAPDCRLMTR-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010981 drying operation Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- JMVWCCOXRGFPJZ-UHFFFAOYSA-N propoxyboronic acid Chemical compound CCCOB(O)O JMVWCCOXRGFPJZ-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- 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)
Abstract
The invention relates to a preparation method of a fluoroquinolone antibacterial drug, particularly a method for preparing moxifloxacin hydrochloride monohydrate disclosed in the specification. The method comprises the following steps: A) dissolving ethyl borate chelate disclosed as Formula (III) in a halohydrocarbon solvent; B) dropwisely adding (S,S)-2,8-diazabicyclo[4.3.0]nonane and organic alkali at the temperature of lower than 30 DEG C; C) heating the reaction mixture, cooling, washing with water and concentrating; and D) dissolving the concentrate in an alcoholic solution, and dropwisely adding concentrated hydrochloric acid. The preparation method lowers the content of major impurities, and especially the content of the impurity-1 disclosed in the specification can be controlled at 0.10% below and preferably 0.05% below.
Description
Technical field
The present invention relates to a kind of preparation method of Moxifloxacin hydrochloride of improvement, it is scorching that described compound is used for the treatment of acute sinus gland, the acute attack of chronic bronchitis, acquired pneumonia, and skin infections etc.
Background technology
Moxifloxacin hydrochloride, its chemistry 1-cyclopropyl-7-{S, S-2,8-diazabicyclo [4.3.0] nonane-8-base by name } the fluoro-8-methoxyl group of-6--4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid hydrochloride, its chemical structure such as formula shown in (Ia),
Moxifloxacin hydrochloride is forth generation Development of Fluoroquinolone Antibacterials, and it has broad-spectrum antibacterial action, is used as the chemotherapeutic of human and animal, effectively can treats the infection that various bacteria causes, also can be used for the anticorrosion of material.
In pharmaceutical preparation, example hydrochloric acid Moxifloxacin sheet, its active constituents of medicine is Moxifloxacin hydrochloride monohydrate, and its structure is such as formula shown in (I):
General Moxifloxacin is generated by the inner complex condensation of compound (S, S)-2,8-diazabicyclo [4.3.0] nonane and compound 1-cyclopropyl base-6,7-difluoro-8-methoxyl-4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid or itself and boric acid.
CN101514201 discloses 1-cyclopropyl-6, 7-difluoro-8-methoxyl-4-oxo-1, 4-dihydro-3-quinoline carboxylic acid ethyl ester prepares the inner complex of corresponding ethyl-borate under zinc chloride exists to boric acid and acetic anhydride, with S, S-2, 8-diazabicyclo [4.3.0] nonane refluxes 3h under the existence of alkali and solvent, evaporated under reduced pressure solvent, resistates adds sherwood oil, filter the NaOH solution that the solid obtained is dissolved in 7%, 3h is stirred at 80 DEG C, filter after being down to room temperature, filtrate is adjusted to neutrality with 5% acetum, filtration drying, obtain Moxifloxacin, yield is 72.6%.
WO2008059223A2 discloses 1-cyclopropyl-6, 7-difluoro-8-methoxyl-4-oxo-1, 4-dihydro-3-quinoline carboxylic acid ethyl ester reacts to boric acid and propionic anhydride the inner complex preparing corresponding boric acid propyl ester, in the presence of an organic base with S, S-2, 8-diazabicyclo [4.3.0] nonane 100 DEG C reaction 3h, use salt acid for adjusting pH to 1.0-2.0 after cooling to 25-30 DEG C, after evaporate to dryness, resistates adds water, pH to 7.5-9.0 is regulated with ammoniacal liquor, solvent evaporated after extraction, resistates dissolve with methanol, salt acid for adjusting pH is to 1.0-2.0, filter, drying under reduced pressure obtains Moxifloxacin hydrochloride, yield is 55.6%.
EP1992626 discloses 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid and S, S-2,8-diazabicyclo [4.3.0] nonane, with DMF or DMSO for solvent, at 65-70 DEG C, react 6-8h, reaction system is cooled to 25-30 DEG C, add water and stir 2h, filtering product washes with water, drying under reduced pressure at 75 DEG C, obtains crude product Moxifloxacin.Be solvent with L (+)-tartrate or fumaric acid with DMF, chiral separation is carried out to Moxifloxacin, removing (R, R) isomer impurities, obtain corresponding Moxifloxacin salt, under room temperature, add concentrated hydrochloric acid, filter, 50-55 DEG C of drying under reduced pressure obtains Moxifloxacin hydrochloride, and yield is 68.8%.
Exist in aforesaid method yield on the low side, need the problems such as chiral separation, had a strong impact on the cost of Moxifloxacin hydrochloride, constrained the industrial production of Moxifloxacin hydrochloride.
Journal of Pharmaceutical and Biomedical Analysis34 (2004) 1125 – 1129 reports separation and the standard method of Moxifloxacin four kinds of major impurities, the present invention reduces the content of major impurity through improving, particularly reduce the content of impurity-1, the moxifloxacin hydrochloride impurity content adopting the present invention to prepare is low, meets pharmaceutical grade USP standard.
Summary of the invention
The object of the invention is on the basis of existing technology, provide that a kind of technique is simple, the content HPLC (peak area) of impurity-1 is less than 0.1%, cost is low, yield is high, be applicable to the preparation method of industrial Moxifloxacin hydrochloride.
Summary of the invention
First aspect present invention provides the preparation method of compound (hereafter claiming the inner complex of ethyl-borate) shown in formula (III),
It comprises: compound shown in formula (II),
With H
3bO
3at anhydrous ZnCl
2under existence, react in diacetyl oxide, it is characterized in that: after completion of the reaction, directly reaction solution is instilled in frozen water, form mixture.
Second aspect present invention provides the method preparing compound shown in moxifloxacin intermediate formula (IV),
It comprises:
A) by the inner complex of ethyl-borate, shown in formula (III), compound dissolution is in halogenated hydrocarbon solvent,
B) dropping (S, S)-2,8-diazabicyclo [4.3.0] nonane and organic bases at 30 DEG C;
C) step B is heated to) backflow of the reaction solution of gained.
Third aspect present invention provides a kind of method preparing Moxifloxacin hydrochloride monohydrate,
Comprise the following steps:
A) inner complex of ethyl-borate, shown in formula (III), compound is dissolved in halogenated hydrocarbon solvent,
B) dropping (S, S)-2,8-diazabicyclo [4.3.0] nonane and organic bases below 30 DEG C; With
C) heat above-mentioned reaction mixture, lower the temperature, wash, concentrate,
D) above-mentioned enriched material is dissolved in alcoholic solution, drips concentrated hydrochloric acid.
Fourth aspect present invention provides a kind of preparation method of stable Moxifloxacin hydrochloride monohydrate, and it comprises:
A) Moxifloxacin hydrochloride of any form is dissolved in purified water, and
B) heating, cooling, crystallization,
C) filter, add dehydrated alcohol making beating.
Term definition
Term " shown in formula (III) compound " refers to that 1-cyclopropyl-6,7-difluoro-8-methoxyls-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid-03,04-bis-acetic acid closes boron ester.
Term " shown in formula (II) compound " refers to 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid ethyl ester.
In contextual content, no matter whether use the wording such as " approximately " or " about ", all numerals disclosed at this are approximation.The numerical value of each numeral likely there will be the difference such as 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%.Whenever disclosing one and having N value digital, any have N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+/-10%, and the digital Hui Bei Ming Indeed ground of N+/-15%or N+/-20% value is open, and wherein " +/-" refers to and add deduct.Whenever disclosing a lower limit in a numerical range, R
l, and a upper limit, R
u, time, the numerical value Hui Bei Ming Indeed within any scope being in the disclosed open.Particularly, the following numerical value within the scope of this is contained: R=R
l+ K
*(R
u-R
l), wherein k be one by 1% increment increase from 1% to 100% variable.As: 1%, 2%, 3%, 4%, 5%...50%, 51%, 52%...95%, 96%, 97%, 98%, 99% or 100%.In addition, also contain especially this disclose above-mentioned with the numerical range of two R definition.
Detailed Description Of The Invention
First aspect present invention provides the preparation method of compound (hereafter claiming the inner complex of ethyl-borate) shown in a kind of formula (III),
It comprises: compound shown in formula (II),
With H
3bO
3at anhydrous ZnCl
2under existence, react in diacetyl oxide, it is characterized in that after completion of the reaction, directly reaction solution is instilled in frozen water, form mixture.
In certain embodiments, adopt HPLC monitoring reaction, when the content of compound in reaction solution formula (II) Suo Shi is less than or equal to 1%, be considered as reaction complete.
In certain embodiments, in the process of reaction solution instillation frozen water, control the temperature of the mixture formed below 20 DEG C.
In certain embodiments, the volume of described frozen water is approximately the 2-5 of diacetyl oxide volume doubly, and in a certain embodiment, the volume of described frozen water is approximately 2 times of diacetyl oxide volume.
In further embodiments, described reaction is carried out at about 70 DEG C to about 100 DEG C, and in a certain embodiment, described reaction is carried out at about 90 DEG C.
After reaction solution dropwises, continue to stir 0.5-24h at about-5 DEG C to about 10 DEG C, filter, be washed to pH=5-7, dry, the inner complex of obtained ethyl-borate.
In certain embodiments, namely the shown compound of the product type (III) of gained directly can carry out next step reaction without the need to being further purified.
Method of the present invention after completion of the reaction, directly reaction solution is instilled in frozen water, can avoid in reaction solution temperature-fall period, solid is separated out, cause being difficult to cooling (if add again in frozen water after reaction solution cooling, the inner complex that just there will be part of boron acetoacetic ester decomposes, and causes technique instability); Due to reacting liquid temperature rapid drawdown, the inner complex of the thinner ethyl-borate of particle can be obtained, do not lump, be convenient to washing, removing acetic acid, thus reduce the decomposition of the inner complex of ethyl-borate.
Second aspect present invention provides the method preparing compound shown in moxifloxacin intermediate formula (IV),
It comprises:
A) by the inner complex of ethyl-borate, shown in formula (III), compound dissolution is in halogenated hydrocarbon solvent,
B) dropping (S, S)-2,8-diazabicyclo [4.3.0] nonane and organic bases at 30 DEG C;
C) above-mentioned reaction solution backflow is heated to.
Steps A) described halogenated hydrocarbon solvent is optional by halogen (F, Cl, Br, I) the C1-C4 alkane replaced or its combination, in certain embodiments, described halogenated hydrocarbon solvent be methylene dichloride, trichloromethane, methylene bromide, tetracol phenixin one or more, in certain embodiments, described halogenated hydrocarbon solvent is methylene dichloride.
Step B) described in organic bases be selected from triethylamine, 1,8-diazacyclo [5,4,0] one or more in-7-hendecene, DIPEA, in certain embodiments, described organic bases is triethylamine, 1, one or more in 8-diazacyclo [5,4,0]-7-hendecene; In further embodiments, described organic bases is for being triethylamine.Shown in formula (III), the mol ratio of compound and organic bases is about 1:0.1 to about 1:2, and being about 1:0.1 to about 1:1.5 in certain embodiments, is about 1:1 in further embodiments.
Step C) described heating be reaction solution is heated to backflow, in certain embodiments, the temperature of described reaction solution is 35 DEG C-50 DEG C, and in further embodiments, the temperature of described reaction solution is 40 DEG C-45 DEG C.
Steps A) described in the inner complex of ethyl-borate can be obtained by the method described in first aspect present invention, also can adopt additive method preparation disclosed in prior art.The inner complex of the ethyl-borate obtained by the method described in first aspect present invention without the need to being further purified, the dry steps A that just can be directly used in second aspect present invention) in, steps A) concrete operation is dissolved in halogenated hydrocarbon solvent by the inner complex wet product of the ethyl-borate obtained by the method described in first aspect present invention, add appropriate water, stir, leave standstill, layering, removing aqueous phase, organic phase cooling after carry out step B) reaction.
Because the dry product taste of the inner complex of ethyl-borate is extremely bitter, there is certain toxicity, the inner complex wet product of the ethyl-borate obtained by the method described in first aspect present invention is directly used in the reaction of the present invention second method, decreases drying operation, and production is amplified in very convenient workshop.
Third aspect present invention provides a kind of method preparing Moxifloxacin hydrochloride monohydrate,
Comprise the following steps:
A) by the inner complex of ethyl-borate, shown in formula (III), compound is dissolved in halogenated hydrocarbon solvent,
B) dropping (S, S)-2,8-diazabicyclo [4.3.0] nonane and organic bases below 30 DEG C; With
C) heat above-mentioned reaction mixture, lower the temperature, wash, concentrate,
D) above-mentioned enriched material is dissolved in alcoholic solution, drips concentrated hydrochloric acid.
Steps A) described halogenated hydrocarbon solvent is the C1-C4 alkane or its combination that are optionally replaced by halogen (F, Cl, Br, I), in certain embodiments, described halohydrocarbon is methylene dichloride, trichloromethane, methylene bromide, tetracol phenixin or its combination.
Step B) described in organic bases be selected from triethylamine, 1,8-diazacyclo [5,4,0] one or more in-7-hendecene, DIPEA, in certain embodiments, described organic bases is triethylamine, 1, one or more in 8-diazacyclo [5,4,0]-7-hendecene; In further embodiments, described organic bases is for being triethylamine.Shown in formula (III), the mol ratio of compound and organic bases is about 1:0.1 to about 1:2, and being about 1:0.1 to about 1:1.5 in certain embodiments, is about 1:1 in further embodiments.
Step C) described heating be reaction solution is heated to backflow, in certain embodiments, the temperature of described reaction solution is 35-50 DEG C.
Step D) described in alcoholic solvent be the lower alcohol of C1-C5, in certain embodiments, described alcoholic solvent be methyl alcohol, ethanol or Virahol or its combination.In certain embodiments, as the pH=1.5-2.0 of reaction solution, start to separate out solid, filter, add dehydrated alcohol making beating and filter, vacuum-drying.
The preparation method of Moxifloxacin hydrochloride monohydrate of the present invention, foreign matter content is low, and particularly the content of impurity-1 can control below 0.10%, and preferably less than 0.05%, HPLC purity is more than 99%, and preferably more than 99.5%, more preferably more than 99.8%,
Be that to prepare HPLC purity of the present invention be the Moxifloxacin hydrochloride of more than 99% to starting material with compound formula (II) Suo Shi, overall yield more than 80%, preferably more than 85%.
Fourth aspect present invention provides a kind of preparation method of stable Moxifloxacin hydrochloride monohydrate, and it comprises:
A) Moxifloxacin hydrochloride of any form is dissolved in purified water, and
B) heating, cooling, crystallization,
C) filter, add dehydrated alcohol making beating.
In certain embodiments, the Moxifloxacin hydrochloride of described any form can be that the Moxifloxacin hydrochloride of 0-1 water is as anhydrous hydrochloric acid Moxifloxacin, a water Moxifloxacin hydrochloride or 0.5 water Moxifloxacin hydrochloride or its combination.
In certain embodiments, described heating refers to and the aqueous solution of Moxifloxacin hydrochloride is heated to more than 80 DEG C, is about 100 DEG C in certain embodiments.
In certain embodiments, described cooling refers to and the aqueous solution of Moxifloxacin hydrochloride is cooled to less than 40 DEG C again after being heated to more than 80 DEG C, is preferably cooled to less than 20 DEG C.
The method preparing Moxifloxacin hydrochloride monohydrate of the present invention, reduce the content of major impurity, particularly reduce the content of impurity-1, the moxifloxacin hydrochloride impurity content adopting the present invention to prepare is low, meet pharmaceutical grade USP standard, preparation method's cost of the present invention is low, yield is high, be applicable to industrial production.
Accompanying drawing explanation
Fig. 1 shows the Moxifloxacin hydrochloride monohydrate prepared by embodiment 5, high performance liquid phase (HPLC) spectrogram of compound shown in formula (1).
Fig. 2 shows the Moxifloxacin hydrochloride monohydrate prepared by embodiment 7, high performance liquid phase (HPLC) spectrogram of compound shown in formula (1).
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, mmol represents mmole, and h represents hour, and g represents gram, and ml represents milliliter.
Embodiment 1 1-cyclopropyl-6,7-difluoro-8-methoxyls-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid-03,04-
Two acetic acid close boron ester (hereafter claiming the inner complex of ethyl-borate), the preparation method of compound shown in formula (III)
Take the anhydrous ZnCl of 1.35g
2, add 231mL Ac
2o, is positioned over flask in alcohol bath, adds 37.78g H
3bO
3, be warming up to 90 DEG C after solution clarification, after stirring 1.5h, add 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid ethyl ester (150g), drops to reaction solution in 462mL frozen water after completion of the reaction, after reaction solution dropwises, filter after continuing to stir 1h at 0 ~ 5 DEG C, washing, dry, obtain the inner complex of ethyl-borate, compound 186.8g shown in formula (III).
Embodiment 2 1-cyclopropyl-6,7-difluoro-8-methoxyls-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid-03,04-
Two acetic acid close boron ester (hereafter claiming the inner complex of ethyl-borate), the preparation method of compound shown in formula (III)
Take anhydrous ZnCl
2(1.35g) 231mL Ac, is added
2o, is positioned over flask in alcohol bath (room temperature, or water-bath), adds H
3bO
3(37.78g), 100 DEG C are warming up to after solution clarification, after stirring 1.5h, add 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid ethyl ester (150g), drops to reaction solution in 460mL frozen water after completion of the reaction, after reaction solution dropwises, after continuing to stir 1h at 0 ~ 5 DEG C, filter, washing, the inner complex wet product of obtained ethyl-borate, wet product not drying is directly used in next step reaction.
Embodiment 3 prepares cyclopropyl-7-(S, S-2,8-diazabicyclo [4.3.0] nonane-8-base) the fluoro-8-methoxy of-6-
Base-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid-03,04-bis-acetic acid closes boron ester, compound shown in formula (IV)
The inner complex wet product of the ethyl-borate prepared by embodiment 2 is dissolved in the CH of 590mL
2cl
2, add 354mL water washing, layering, aqueous phase discards, and organic phase is cooled to 10 DEG C, drips (S, S)-2,8-diazabicyclos [4.3.0] nonane (65.63g), adds 47.56g triethylamine, be heated to backflow, react complete, be down to room temperature, add 354mL water, layering, organic phase evaporated under reduced pressure, is directly used in next step reaction.
Embodiment 4 prepares cyclopropyl-7-(S, S-2,8-diazabicyclo [4.3.0] nonane-8-base) the fluoro-8-methoxyl group of-6-
-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid-03,04-bis-acetic acid closes boron ester, compound shown in formula (IV)
The inner complex of ethyl-borate, shown in formula (III), compound (168.8g) is dissolved in the CH of 590mL
2cl
2be cooled to about 10 DEG C, drip (S, S)-2,8-diazabicyclo [4.3.0] nonane (65.6g), add 47.56g triethylamine, be warming up to backflow, after completion of the reaction, be down to room temperature, add 354mL water washing, layering, organic phase evaporated under reduced pressure obtains compound 190.4g shown in formula (IV).
Embodiment 5 prepares Moxifloxacin hydrochloride monohydrate, compound shown in formula (1)
The EtOH of 671ml is added in the compound formula prepared by embodiment 3 (IV) Suo Shi, concentrated hydrochloric acid 43.0mL is dripped under room temperature, with accurate pH test paper monitoring reaction solution pH=1.5-2.0, solid starts to separate out, filter, add dehydrated alcohol 600mL, pull an oar 1h under room temperature, filter, at 50 DEG C, vacuum-drying 14h, obtains Moxifloxacin hydrochloride, compound shown in formula (1), yield 85%, HPLC purity (peak area) is 99.878%, and in accompanying drawing 1, the retention time (RT) of impurity-1 is 13.51.
Table one: the peak area that accompanying drawing 1 retention time is corresponding
| RT (retention time) | Peak area (%) |
| 10.66 | 0.007 |
| 13.51 | 0.086 |
| 15.22 | 99.878 |
| 22.08 | 0.006 |
| 23.14 | 0.016 |
| 41.76 | 0.002 |
| 49.32 | 0.004 |
Embodiment 6 prepares Moxifloxacin hydrochloride monohydrate, compound shown in formula (1)
671ml EtOH is added in compound (190.4g) formula prepared by embodiment 4 (IV) Suo Shi, drip concentrated hydrochloric acid 43.0mL under room temperature, with accurate pH test paper monitoring reaction solution pH=1.5-2.0, solid starts to separate out, filter, add dehydrated alcohol 600mL, pull an oar 1h under room temperature, filters, vacuum-drying 14h at 50 DEG C, obtain Moxifloxacin hydrochloride, compound shown in formula (1), yield 90%.
Embodiment 7 purifying Moxifloxacin hydrochloride monohydrate, compound shown in formula (1)
By the Moxifloxacin hydrochloride monohydrate that 182g is prepared by embodiment 5 or 6, shown in formula (1), compound is dissolved in 1.0L purified water, is warming up to 100 DEG C, solution becomes clarification, and slow cooling, to about 10 DEG C, is incubated 2h, filter, add dehydrated alcohol 450mL, in room temperature making beating 1h, filter, at 50 DEG C, vacuum-drying 7h, obtains Moxifloxacin hydrochloride, compound 151.3g shown in formula (1), yield 90%, HPLC purity 99.967%, KF=3.973%, Residual ethanol is 17.85ppm.In accompanying drawing 2, the retention time (RT) of impurity-1 is 12.79
Table two: the peak area that accompanying drawing 2 retention time is corresponding
| RT (retention time) | Peak area (%) |
| 3.29 | 0.003 |
| 12.79 | 0.030 |
| 14.30 | 99.967 |
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (12)
1. a preparation method for compound shown in formula (III),
It comprises: compound shown in formula (II),
With H
3bO
3at anhydrous ZnCl
2under existence, react in diacetyl oxide, it is characterized in that after completion of the reaction, directly reaction solution is instilled in frozen water, form mixture.
2. preparation method according to claim 1, the volume of described frozen water is 2-5 times of diacetyl oxide volume.
3. preparation method according to claim 1 and 2, described reaction is carried out at 70-100 DEG C, or carries out at about 90 DEG C.
4., according to the arbitrary described preparation method of claim 1-3, in the process of reaction solution instillation frozen water, control the temperature of the mixture formed below 20 DEG C.
5. prepare a method for compound shown in moxifloxacin intermediate formula (IV),
It comprises:
A) by compound dissolution formula (III) Suo Shi in halogenated hydrocarbon solvent,
B) dropping (S, S)-2,8-diazabicyclo [4.3.0] nonane and organic bases at 30 DEG C;
C) above-mentioned reaction solution backflow is heated to.
6. preparation method according to claim 5, steps A) described halogenated hydrocarbon solvent is optionally by C1-C4 alkane or its combination of halogen substiuted, or steps A) described halogenated hydrocarbon solvent is methylene dichloride.
7. the preparation method according to claim 5 or 6, steps A) concrete way is that the wet product of the inner complex of ethyl-borate method according to claim 1 obtained is dissolved in halogenated hydrocarbon solvent, add appropriate water, stir, leave standstill, layering, removing aqueous phase, organic phase cooling after carry out step B) reaction.
8., according to the arbitrary described preparation method of claim 5-7, the mol ratio of compound and organic bases shown in formula (III) is about 1:0.1 to about 1:2.
9. prepare a method for Moxifloxacin hydrochloride monohydrate formula (I),
Comprise the following steps:
A) by the inner complex of ethyl-borate, shown in formula (III), compound is dissolved in halogenated hydrocarbon solvent,
B) dropping (S, S)-2,8-diazabicyclo [4.3.0] nonane and organic bases below 30 DEG C; With
C) heat above-mentioned reaction mixture, lower the temperature, wash, concentrate,
D) above-mentioned enriched material is dissolved in alcoholic solution, drips concentrated hydrochloric acid.
10. a stable Moxifloxacin hydrochloride monohydrate, the preparation method of compound shown in formula (I), it comprises:
A) Moxifloxacin hydrochloride of any form is dissolved in purified water, and
B) heating, cooling, crystallization,
C) filter, add dehydrated alcohol making beating.
11. preparation methods according to claim 10, described step B) described in heating refer to steps A) aqueous solution of Moxifloxacin hydrochloride that formed is heated to more than 80 DEG C.
12. preparation methods according to claim 10 or 11, described cooling refers to and the aqueous solution of Moxifloxacin hydrochloride is cooled to less than 40 DEG C again after being heated to more than 80 DEG C.
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