CN115536658A - Preparation method of moxifloxacin hydrochloride monohydrate - Google Patents
Preparation method of moxifloxacin hydrochloride monohydrate Download PDFInfo
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- CN115536658A CN115536658A CN202211101004.XA CN202211101004A CN115536658A CN 115536658 A CN115536658 A CN 115536658A CN 202211101004 A CN202211101004 A CN 202211101004A CN 115536658 A CN115536658 A CN 115536658A
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- 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 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000012535 impurity Substances 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 238000005580 one pot reaction Methods 0.000 claims abstract description 7
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- 230000003197 catalytic effect Effects 0.000 claims abstract description 3
- 230000009920 chelation Effects 0.000 claims abstract description 3
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- WQJZXSSAMGZVTM-UHFFFAOYSA-N 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound COC1=C(F)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 WQJZXSSAMGZVTM-UHFFFAOYSA-N 0.000 claims description 8
- 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 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000004327 boric acid Substances 0.000 claims description 4
- 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 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 3
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims 1
- 238000001514 detection method Methods 0.000 abstract description 8
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 description 14
- 230000008569 process Effects 0.000 description 14
- 229960003702 moxifloxacin Drugs 0.000 description 13
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 description 13
- 239000013078 crystal Substances 0.000 description 11
- 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 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
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- 229910052796 boron Inorganic materials 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- -1 salifying Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-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
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 125000005233 alkylalcohol group Chemical group 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004042 decolorization Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000036209 Intraabdominal Infections Diseases 0.000 description 1
- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 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
- 230000009466 transformation Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of raw material medicine synthesis, and particularly relates to a preparation method of moxifloxacin hydrochloride monohydrate. The preparation method comprises the steps of taking Lewis acid as Sub>A catalyst, taking TF-A as Sub>A raw material, carrying out chelation reaction on the TF-A under the catalytic action to generate Sub>A TF-B intermediate, and carrying out condensation, hydrolysis, salification and impurity removal on the TF-B by adopting Sub>A one-pot method to obtain the high-purity moxifloxacin hydrochloride monohydrate. The preparation method provided by the application has the advantages of mild reaction conditions, easily controlled production process, batch and continuous production, no enantiomer is produced in the reaction process, and no chiral resolving agent is required to be added. The product quality is high by combining related detection results, the single impurity is less than or equal to 0.05 percent, the total impurity is less than or equal to 0.1 percent, the purity of the moxifloxacin hydrochloride monohydrate is up to more than 99.90 percent, the product stability is good, the moxifloxacin hydrochloride monohydrate can be directly used as a raw material medicine to be fed for producing and preparing a finished medicament, and the product has good production advantages.
Description
Technical Field
The invention belongs to the technical field of raw material medicine synthesis, and particularly relates to a preparation method of moxifloxacin hydrochloride monohydrate.
Background
Moxifloxacin Hydrochloride (Moxifloxacin Hydrochloride), chemical name is: 1-cyclopropyl-6-fluoro-8-methoxy-7- [ (4 aS,7 aS) -octahydro-6H-pyrrolo [3,4-b ] pyridin-6-yl ] -4-oxo-1,4-dihydro-3-quinoline carboxylic acid hydrochloride, first marketed in Germany in 1999.
Moxifloxacin is a broad-spectrum antibacterial drug and is mainly used for treating various diseases caused by sensitive bacteria, such as: acute bacterial sinusitis, acute episodes of chronic bronchitis, community-acquired pneumonia, uncomplicated skin and skin tissue infections, complicated intra-abdominal infections, and the like. The antibacterial agent has the advantages of strong antibacterial activity, wide antibacterial spectrum, difficult generation of drug resistance, effectiveness to common drug-resistant bacteria, long half-life period, few adverse reactions and the like, so the clinical application is very common.
In industrial production, mo Xing moxifloxacin is generally prepared from: the compound (s, s) -2,8-diazabicyclo [4.3.0] nonane + the compound 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid or its chelate with boronic acid is condensed. The prior art refers to the following part of the synthetic process routes:
in chinese patent CN103626768, it adopts: 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4 dihydro-4-oxoquinoline-3-carboxylic acid-O3, O4-diacetic acid boric acid ester (A) + (s, s) -2,8 diazabicyclo [4,3,0] nonane (B), reacting to prepare moxifloxacin, and then synthesizing moxifloxacin hydrochloride by using moxifloxacin. Wherein, the moxifloxacin is firstly hydrolyzed by sodium hydroxide solution, then the impurities are extracted by ethyl acetate, and then the pH value is adjusted by hydrochloric acid, salifying, crystal transformation, cooling crystallization, filtration and drying are carried out, thus finally obtaining the moxifloxacin hydrochloride. But in combination with the practical effect, the method only obtains the finished moxifloxacin hydrochloride product with the purity of about 98 percent, and is difficult to meet the requirement of the pharmaceutical industry of China on high-quality products.
In chinese patent CN103172629a, a synthesis method of high-purity moxifloxacin hydrochloride is provided: 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4 dihydro-4-oxoquinoline-3-carboxylic acid-O3, O4-diacetic acid borate (A) + (s, s) -2,8 diazabicyclo [4,3,0] nonane (B), after the reaction is finished, evaporating the solvent, dissolving the residue with ethanol, adjusting the pH to acidity with concentrated hydrochloric acid, cooling for crystallization, and filtering to obtain a crude moxifloxacin hydrochloride; dissolving the crude moxifloxacin hydrochloride with alkali liquor, extracting with an organic solvent for three times, adding concentrated hydrochloric acid into a water layer to adjust the pH value to 1-5, crystallizing, filtering, recrystallizing the obtained filter cake with a water-containing organic solvent, and finally filtering and drying to obtain the high-purity moxifloxacin hydrochloride. However, in combination with the actual industrialized production factors, the process has too many post-treatment steps and too complex operation, and has great influence on the subsequent yield and output, so that the process is not suitable for the actual industrialized production needs.
For finished products of moxifloxacin hydrochloride, patents US5849752 and CN1160052 report two finished product forms of anhydrous crystal form and hydrous crystal form of moxifloxacin. Wherein: the anhydrous crystal form is unstable under conventional storage and preparation conditions due to strong hygroscopicity, and is easy to absorb moisture, so that the accuracy of dosage and the quality of the preparation are directly influenced. The hydrous crystal form is a relatively stable form, so that the active pharmaceutical ingredient in the actual finished medicament product is presented in the form of moxifloxacin hydrochloride monohydrate.
For the preparation of moxifloxacin hydrochloride monohydrate, WO2008138759 discloses a preparation method of moxifloxacin hydrochloride monohydrate, which comprises the following steps: 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and S, S-2,8-diazabicyclo [4.3.0] nonane are used as raw materials, firstly reacted in DMF or DMSO to generate moxifloxacin, then salified and purified with L (+) -tartaric acid (or fumaric acid, or L-2-p-methylbenzoyl tartaric acid) in DMF, and finally treated with concentrated hydrochloric acid in a mixed solvent of ethanol and water to obtain moxifloxacin monohydrate. After analysis, the method needs chiral resolution, and the used solvent DMF or DMSO has high boiling point and is difficult to recover, which is not beneficial to solvent recovery in actual industrial production, therefore, the method is not suitable for industrial and industrialized production.
In patent CN102344447, a method for preparing moxifloxacin monohydrate is introduced, which comprises the steps of firstly dissociating moxifloxacin from moxifloxacin hydrochloride by using saturated sodium hydroxide, and then converting moxifloxacin into moxifloxacin hydrochloride monohydrate under a proper aqueous solvent or environment, but the method needs to perform 'rework' treatment on moxifloxacin hydrochloride to prepare moxifloxacin, so that the production cost is increased invisibly, and the method cannot be practically used for industrial production.
Disclosure of Invention
On the basis of research on a moxifloxacin synthesis process and by combining with the actual industrialized production, the application aims to provide a preparation method of moxifloxacin hydrochloride monohydrate with high yield and high purity, so that a certain technical basis is laid for the industrialized preparation of moxifloxacin hydrochloride monohydrate.
The technical scheme provided by the application is specifically introduced as follows.
A preparation method of moxifloxacin hydrochloride monohydrate comprises the following steps: taking Lewis acid as Sub>A catalyst, taking TF-A (1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester) as Sub>A raw material, carrying out Sub>A chelation reaction on TF-A under the catalytic action to generate Sub>A TF-B (1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3, O4-boron diacetate) intermediate, and then carrying out condensation, hydrolysis, salt formation and impurity removal on TF-B by adopting Sub>A one-pot method to obtain high-purity moxifloxacin hydrochloride monohydrate; the method specifically comprises the following steps:
(I) synthetic preparation of TF-B intermediate
(1) Firstly, in a reaction vessel, reacting acetic anhydride, boric acid and a catalyst reaction system at 105-120 ℃ for 0.5-3h (in order to ensure full reaction, the reaction system is stirred in a proper amount at proper time in the reaction process); after the reaction is finished, cooling to 30-80 ℃ for later use;
the catalyst is as follows: one or a mixture of more of BF3, feCl3, alCl3, znCl2 and SnCl4 of Lewis acid in any proportion;
(2) Then, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester (TF-A) is added to react at 105-120 ℃ for 2~5 hours, so that the reaction is fully ensured (thin layer chromatography (TLC) can be adopted, and ethyl acetate is used as Sub>A developing agent to detect until TF-A raw materials disappear);
TF-A: catalyst =1: (0.0065 + -0.002);
(3) Finally, after the reaction system is naturally cooled (the temperature is reduced to 50-80 ℃), transferring the reaction system into ice water to quench the reaction system for 1-2 hours (the reaction system can be stirred in due time and in a proper amount), centrifugally throwing and filtering the reaction system, washing and drying a filter cake by purified water to obtain a yellow solid TF-B intermediate (1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3, O4-boron diacetate);
the determination shows that under the process conditions, the mass yield is as follows: 126 to 131 percent; molar yield: 96% -100%;
(II) one-pot method for preparing high-purity moxifloxacin hydrochloride monohydrate
(1) Firstly, adding the TF-B intermediate obtained in the step (1), an organic base and TF-C ((S, S) -2,8-diazabicyclo [4,3,0] nonane) into an organic solvent (such as acetonitrile), heating and refluxing to react until the reaction is finished (thin layer chromatography (TLC) can be adopted, and the reaction is ensured to be finished by using methanol: dichloromethane =4:1 as a developing agent);
the organic base is: one or a mixture of more of triethylamine, dipropylamine, tert-butylamine, pyridine, DMAP and DIPEA in any proportion;
(2) Then adding activated carbon (2-5 percent by mass) for decoloring for 30-60 min, and filtering while the solution is hot;
(3) Then, adding an alkanol solvent into the filtrate, dropwise adding hydrochloric acid, and stirring for 2 hours after dropwise adding;
the hydrochloric acid is hydrochloric acid with the concentration of 5-12 mol/L;
the alcohol solvent is: one or a mixture of more than one of C1-C4 alkanol solvents in any proportion;
and (3) the TF-B intermediate is calculated according to the mass ratio: alkanol solvent =1: (2-10);
(4) Then adding an impurity-removing solvent, after the addition is finished, heating, keeping the temperature for 10 to 60min, and then carrying out gradient cooling to-10 ℃ and continuously stirring for 4-6 hours;
the impurity removal solvent is: one or a mixture of more of C1-C4 alkanol solvent, acetone, ethyl acetate, acetonitrile and THF in any proportion;
the mass ratio of the TF-B intermediate is as follows: impurity removal solvent =1: (2-10);
the temperature rise refers to the temperature rise to 40-90 ℃; the temperature is kept for a certain time after being increased, so that impurities in the reaction system are effectively removed by using an impurity removal solvent;
the gradient cooling means that the cooling rate is 5-15 ℃/h;
(5) Finally, carrying out solid-liquid separation, leaching the filter cake with an impurity-removing solvent, and drying to obtain a finished product of the moxifloxacin hydrochloride monohydrate;
the drying mode can adopt forced air drying or vacuum drying, the drying temperature is generally 10-60 ℃, and the drying time is generally 4-24 hours;
according to the process route provided by the application, TF-A is used as Sub>A starting material, and the moxifloxacin hydrochloride monohydrate is prepared by chelating, condensing, hydrolyzing to form hydrochloride and removing impurities. By analyzing the process route, compared with other existing process routes, the preparation method of moxifloxacin hydrochloride monohydrate provided by the application has the following advantages: the adoption of the one-pot method can greatly simplify the preparation process of the moxifloxacin hydrochloride; the method can be used for continuous production without excessive separation and purification, thereby being beneficial to reducing the loss of raw materials and products, improving the yield, reducing and reducing the labor intensity, improving the operation production environment and reducing the industrial production cost.
Generally, the preparation method provided by the application has the advantages of mild reaction conditions, easily controlled production process, batch and continuous production, no enantiomer is generated in the reaction process, and no chiral resolving agent is required to be added. The product has high quality, single impurity content not more than 0.05% (no impurity peak greater than 0.05% in the finished product can be seen from the HPLC detection result of the finished product), total impurity content not more than 0.1%, moxifloxacin hydrochloride monohydrate purity more than 99.90%, good product stability, and can be directly used as a raw material medicament for producing and preparing finished medicaments, thus showing better production advantages.
Drawings
FIG. 1 shows the HPLC detection results of moxifloxacin hydrochloride monohydrate prepared in example 1;
FIG. 2 is an XRD spectrum of a finished moxifloxacin hydrochloride monohydrate prepared in example 1;
FIG. 3 is the HPLC detection result of moxifloxacin hydrochloride monohydrate prepared in example 2;
FIG. 4 is an XRD spectrum of a finished moxifloxacin hydrochloride monohydrate prepared in example 2;
FIG. 5 shows the HPLC detection result of moxifloxacin hydrochloride monohydrate prepared in example 3;
FIG. 6 is the XRD spectrum of the finished moxifloxacin hydrochloride monohydrate prepared in example 3.
Detailed Description
The present application is further illustrated by the following examples.
Example 1
Taking the specific material dosage as an example, the preparation process of the moxifloxacin hydrochloride monohydrate is explained in detail as follows.
(I) synthetic preparation of TF-B intermediate
(1) Firstly, 480g of acetic anhydride, 145g of boric acid and 3.5g of catalyst (anhydrous zinc chloride) are stirred and reacted for 1.5 hours at the temperature of 110 ℃ in a reaction vessel; after the reaction is finished, cooling to about 60 ℃ for later use;
(2) Subsequently, 500g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (TF-A) was added and reacted at 110 ℃ for 4 hours to ensure sufficient reaction (thin layer chromatography TLC with ethyl acetate as Sub>A developing agent until TF-A material disappeared);
TF-A: catalyst =1: (0.0065 + -0.002);
(3) Finally, after the reaction system is naturally cooled (to about 60 ℃), transferring the reaction system into water to stir and quench for 2 hours, centrifugally filtering, washing a filter cake with purified water, and drying to obtain a yellow solid TF-B intermediate (1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid-O3, O4-boron diacetate);
weighing indicates that after drying, 640.5g yellow solid TF-B is obtained altogether, and after calculation, the mass yield is 128.1%.
(II) one-pot method for preparing high-purity moxifloxacin hydrochloride monohydrate
(1) Firstly, 100g of TF-B intermediate obtained in the step (1), organic base (29 g of triethylamine) and 35g of TF-C ((S, S) -2,8-diazabicyclo [4,3,0] nonane) are added into 250g of organic solvent acetonitrile, and after uniform mixing, the temperature is increased and the reflux reaction is carried out until the reaction is terminated (thin layer chromatography TLC is adopted, methanol: dichloromethane =4:1 is used as a developing agent to detect and ensure the reaction to be terminated);
(2) Then, 2.5g of activated carbon is added for decolorization for 45min, and the mixture is filtered while the mixture is hot;
(3) Then, adding an alkanol solvent methanol (300 g) into the filtrate, dropwise adding hydrochloric acid (6 mol/L concentration) to adjust the pH to be 1.5, and stirring for 2 hours after dropwise adding;
(4) Then, adding an impurity removal solvent (400 g of acetone), after the addition is finished, heating to 40 ℃, preserving the temperature for 30min, carrying out gradient cooling to about 4 ℃ at a cooling rate of 8 ℃/h, and continuously stirring for 4 hours;
(5) Finally, carrying out solid-liquid separation, leaching the filter cake with an impurity-removing solvent (acetone), and drying to obtain a finished product of the yellow moxifloxacin hydrochloride monohydrate;
the drying can be realized by adopting a forced air drying mode, the drying temperature is 50 ℃, and the drying time is 10 hours;
weighing and calculation show that 93.5g of finished product of moxifloxacin hydrochloride monohydrate (the water content is 4.2%) is obtained, and the mass yield is 93.5%.
The HPLC detection result of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in figure 1, and the purity of the moxifloxacin hydrochloride monohydrate finished product is 99.95 percent.
The XRD spectrogram of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in figure 2, and the XRD spectrogram has characteristic sharp diffraction peaks at positions of 2 theta =5.74,8.40, 10.01, 14.10, 16.88, 17.30, 20.30, 23.52, 23.99, 26.68, 27.40 and the like, and compared with the existing literature values, the crystal form of the moxifloxacin hydrochloride monohydrate finished product is consistent with the crystal form of the original ground monohydrate.
On the basis of the process parameters, a single-factor adjustment experiment is carried out on part of the process parameters in the preparation process of the moxifloxacin hydrochloride monohydrate, and the specific test results are shown in the following table 1.
TABLE 1 investigation of some process parameters during the preparation of moxifloxacin hydrochloride monohydrate
Note: when the crystallization temperature is inspected, gradient cooling treatment is not adopted, and only a single temperature range treatment result is obtained.
Based on the results in the table, it can be seen that the optimized experimental process parameters have relatively optimal preparation effects.
Example 2
The preparation process of the finished moxifloxacin hydrochloride monohydrate prepared in the embodiment is substantially the same as that of the finished moxifloxacin hydrochloride hydrate prepared in the embodiment 1, and only part of process parameters are adjusted, specifically:
the preparation of the TF-B intermediate in step (one) is the same as in example 1;
in the step (II):
(1) 125g of TF-B intermediate, 37g of dipropylamine and 45g of TF-C are added into 320g of acetonitrile for reaction;
(2) Adding 3.0g of activated carbon for decoloring for 50min;
(3) The alkyl alcohol solvent is 350g of methanol; the hydrochloric acid is 5mol/L hydrochloric acid, and the pH is adjusted to be =1.5;
(4) The impurity removal solvent adopts 550g of acetone, the temperature is raised to 50 ℃, then the temperature is kept for 1h, the temperature reduction rate is 10 ℃/h, the temperature is reduced to about 2 ℃, and the stirring is continued for 4 h;
(5) Finally, carrying out solid-liquid separation, leaching the filter cake with an impurity-removing solvent (acetone), and drying to obtain a finished product of the yellow moxifloxacin hydrochloride monohydrate;
the drying can be realized by adopting a forced air drying mode, the drying temperature is 50 ℃, and the drying time is 10 hours;
weighing and calculation show that 116.1g of finished product of moxifloxacin hydrochloride monohydrate (the water content is 4.5%) is obtained, and the mass yield is 92.9%.
The HPLC detection result of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in figure 3, and the purity of the moxifloxacin hydrochloride monohydrate finished product is 99.96%.
The XRD spectrogram of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in figure 4, and the XRD spectrogram has characteristic sharp diffraction peaks at positions of 2 theta =5.74,8.41, 10.01, 14.41, 16.90, 17.36, 20.29, 23.56, 24.03, 26.39, 27.40 and the like, and compared with the existing literature values, the crystal form of the moxifloxacin hydrochloride monohydrate finished product is consistent with the crystal form of the original ground monohydrate.
Example 3
The preparation process of the finished moxifloxacin hydrochloride monohydrate prepared in the embodiment is substantially the same as that of the finished moxifloxacin hydrochloride hydrate prepared in the embodiment 1, and only part of process parameters are adjusted, specifically:
the preparation of the TF-B intermediate in step (one) is the same as in example 1;
in the step (II):
(1) 200g of TF-B intermediate, an organic base (41.5 g of tert-butylamine) and 70.5g of TF-C are added into 500g of acetonitrile to react;
(2) Adding 5.0g of activated carbon for decolorization for 60min;
(3) The alkyl alcohol solvent is 620g of methanol; the hydrochloric acid is 5mol/L hydrochloric acid, and the pH is adjusted to be =2.0;
(4) Removing impurities with 900g acetone, heating to 60 deg.C, maintaining the temperature for 1h at a cooling rate of 8 deg.C/h, cooling to about 5 deg.C, and stirring for 4 hr;
(5) Finally, carrying out solid-liquid separation, leaching the filter cake with an impurity-removing solvent (acetone), and drying to obtain a finished product of the yellow moxifloxacin hydrochloride monohydrate;
the drying can be realized by adopting a forced air drying mode, the drying temperature is 50 ℃, and the drying time is 10 hours;
weighing and calculation show that 187.5g of finished product of the moxifloxacin hydrochloride monohydrate (the water content is 4.3%) is obtained together, and the mass yield is 93.8%.
The HPLC detection result of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in figure 5, and the purity of the moxifloxacin hydrochloride monohydrate finished product is 99.95 percent.
The XRD spectrogram of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in figure 6, and characteristic sharp diffraction peaks are found at positions of 2 theta =5.75,8.43, 10.02, 14.41, 16.92, 17.35, 20.29, 23.56, 24.02, 26.40, 27.42 and the like in the XRD spectrogram, compared with the existing literature values, the crystal form is consistent with the crystal form of the original ground monohydrate.
Claims (7)
1. A preparation method of moxifloxacin hydrochloride monohydrate is characterized in that Lewis acid is used as Sub>A catalyst, TF-A is used as Sub>A raw material, the TF-A is subjected to chelation reaction under the catalytic action to generate Sub>A TF-B intermediate, and then the TF-B is subjected to condensation, hydrolysis, salification and impurity removal by adopting Sub>A one-pot method to obtain high-purity moxifloxacin hydrochloride monohydrate;
the TF-A is: 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester;
the TF-B is: 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid O3, O4-borodiacetate;
the preparation method specifically comprises the following steps:
(I) synthetic preparation of TF-B intermediate
(1) Firstly, in a reaction vessel, reacting acetic anhydride, boric acid and a catalyst reaction system at 105-120 ℃ for 0.5-3h;
the catalyst is Lewis acid;
(2) Then, adding TF-A, and reacting for 2~5 hours at 105-120 ℃ to ensure full reaction;
(3) Finally, after the reaction system is naturally cooled, transferring the reaction system into ice water for quenching, centrifugally filtering, washing and drying a filter cake to obtain a yellow solid TF-B intermediate;
(II) one-pot method for preparing high-purity moxifloxacin hydrochloride monohydrate
(1) Firstly, adding the TF-B intermediate obtained in the step (1), organic base and TF-C into an organic solvent, heating, and carrying out reflux reaction until the reaction is terminated;
the TF-C is: (S, S) -2,8-diazabicyclo [4,3,0] nonane;
the organic base is: one or a mixture of more of triethylamine, dipropylamine, tert-butylamine, pyridine, DMAP and DIPEA in any proportion;
(2) Then adding activated carbon for decoloring and filtering;
(3) Then, adding an alkanol solvent into the filtrate, dropwise adding hydrochloric acid, and stirring to react fully after dropwise adding;
the alcohol solvent is: one or a mixture of more than one of C1-C4 alkanol solvents in any proportion;
(4) Then adding an impurity removal solvent, after the addition is finished, heating, keeping the temperature for 10 to 60min, and then carrying out gradient cooling to-10 ℃ and continuing stirring for 4-6 hours;
the impurity removal solvent is: one or a mixture of more of C1-C4 alkanol solvent, acetone, ethyl acetate, acetonitrile and THF in any proportion;
the temperature rise refers to the temperature rise to 40-90 ℃;
(5) And finally, carrying out solid-liquid separation, leaching the filter cake with an impurity-removing solvent, and drying to obtain a finished product of the yellow moxifloxacin hydrochloride monohydrate.
2. The process for preparing moxifloxacin hydrochloride monohydrate according to claim 1, characterized by the steps of (A)In one), the catalyst is BF3 and FeCl in Lewis acid 3 、AlCl 3 、ZnCl 2 、SnCl 4 One or a mixture of several of them in any proportion.
3. The method for preparing moxifloxacin hydrochloride monohydrate according to claim 1, wherein in the step (one), the mass ratio of TF-A: catalyst =1: (0.0065. + -. 0.002).
4. The method for preparing moxifloxacin hydrochloride monohydrate according to claim 1, wherein in the step (two), the hydrochloric acid is hydrochloric acid with a concentration of 5 to 12 mol/L;
and (3) the TF-B intermediate is calculated according to the mass ratio: alkanol solvent =1: (2-10).
5. The method for preparing moxifloxacin hydrochloride monohydrate according to claim 1, wherein in the step (two), the organic solvent is acetonitrile.
6. The method for preparing moxifloxacin hydrochloride monohydrate according to claim 1, wherein in the step (two), the mass ratio of the TF-B intermediate: impurity removal solvent =1: (2-10).
7. The method for preparing moxifloxacin hydrochloride monohydrate according to claim 1, wherein in the step (II), the temperature is raised to 40 ℃ and then is preserved for 30min.
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