CN115536658B - Preparation method of moxifloxacin hydrochloride monohydrate - Google Patents
Preparation method of moxifloxacin hydrochloride monohydrate Download PDFInfo
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- CN115536658B CN115536658B CN202211101004.XA CN202211101004A CN115536658B CN 115536658 B CN115536658 B CN 115536658B CN 202211101004 A CN202211101004 A CN 202211101004A CN 115536658 B CN115536658 B CN 115536658B
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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 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 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 25
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 238000005580 one pot reaction Methods 0.000 claims abstract description 7
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- 230000009920 chelation Effects 0.000 claims abstract description 4
- 238000006555 catalytic 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 29
- 239000000047 product Substances 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 13
- 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
- 239000000203 mixture Substances 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 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
- 239000004327 boric acid Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 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
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052796 boron Inorganic materials 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
- 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
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 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 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims 2
- 238000001514 detection method Methods 0.000 abstract description 13
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 238000010924 continuous production Methods 0.000 abstract description 3
- 238000010923 batch production Methods 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 229960003702 moxifloxacin Drugs 0.000 description 15
- 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 14
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000009776 industrial production 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
- 239000013078 crystal Substances 0.000 description 6
- 150000004682 monohydrates Chemical class 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 238000007605 air drying Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000001105 regulatory effect Effects 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 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
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- -1 moxifloxacin monohydrate Chemical class 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010059866 Drug resistance 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
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient 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
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 229910052956 cinnabar Inorganic materials 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
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 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
- 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
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—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 application belongs to the technical field of raw material medicine synthesis, and particularly relates to a preparation method of moxifloxacin hydrochloride monohydrate. The preparation method takes Lewis acid as Sub>A catalyst, takes TF-A as Sub>A raw material, takes TF-A to generate chelation reaction under the catalysis to generate TF-B intermediate, and adopts Sub>A one-pot method to obtain high-purity moxifloxacin hydrochloride monohydrate by condensing, hydrolyzing, salifying and removing impurities of TF-B. The preparation method provided by the application has the advantages of mild reaction conditions, easy control of the production process, batch and continuous production, no enantiomer in the reaction process, and no need of adding chiral resolving agent. By combining related detection results, the product quality is high, single impurity is less than or equal to 0.05%, total impurity is less than or equal to 0.1%, the purity of moxifloxacin hydrochloride monohydrate is as high as more than 99.90%, and the product stability is good, so that the moxifloxacin hydrochloride monohydrate can be directly used as a raw material for producing and preparing finished products of medicaments, and 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: 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 carboxylate, was first marketed in 1999 in germany.
Moxifloxacin is used as a broad-spectrum antibacterial agent, 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, non-complex skin and skin tissue infections, complex intraperitoneal infections, and the like. The preparation has the advantages of strong antibacterial activity, broad antibacterial spectrum, difficult generation of drug resistance, effective on common drug-resistant bacteria, long half-life period, less adverse reaction and the like, and is very popular in clinical application.
In industrial production, mo Xingmo cinnabar is generally produced by: the compound (s, s) -2, 8-diazabicyclo [4.3.0] nonane+ compound 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinoline carboxylic acid or chelate thereof with boric acid. The partial synthetic process routes in the prior art are referenced below:
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) is reacted to prepare moxifloxacin, and moxifloxacin hydrochloride is synthesized by using moxifloxacin. Wherein, the moxifloxacin is hydrolyzed by sodium hydroxide solution, then the ethyl acetate is used for extracting impurities, then the hydrochloric acid is used for adjusting the pH value, salifying, crystal transformation, cooling and crystallization, filtering and drying, and finally the moxifloxacin hydrochloride is obtained. But combining with the practical effect, the method only obtains the moxifloxacin hydrochloride finished product with the purity of about 98 percent, and hardly meets the requirements of the medical industry in China on high-quality products.
In chinese patent CN103172629a, a method for synthesizing 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 boric acid ester (A) + (s, s) -2,8 diazabicyclo [4,3,0] nonane (B), evaporating the solvent after the reaction is finished, dissolving the residue with ethanol, regulating the pH value to be acidic with concentrated hydrochloric acid, cooling for crystallization, and filtering to obtain a moxifloxacin hydrochloride crude product; dissolving moxifloxacin hydrochloride crude product with alkali liquor, extracting for three times with an organic solvent, adding concentrated hydrochloric acid into a water layer to adjust the pH value to 1-5, crystallizing, filtering, recrystallizing the obtained filter cake with an aqueous organic solvent, and finally filtering and drying to obtain the high-purity moxifloxacin hydrochloride. However, in combination with practical industrial production factors, the post-treatment steps of the process are too many, the operation is too complicated, and the subsequent yield and the output are greatly influenced, so that the process is not suitable for practical industrial production requirements.
For finished moxifloxacin hydrochloride, patent US5849752, CN1160052 report two finished forms, an anhydrous crystalline form and an aqueous crystalline form of moxifloxacin. Wherein: the anhydrous crystal form is unstable under the conventional storage and preparation conditions due to the strong hygroscopicity, and is easy to absorb moisture, so that the dosage accuracy and the quality of the preparation are directly affected. The aqueous crystalline form is a relatively stable form, and therefore, in the actual pharmaceutical product, the pharmaceutically active ingredient is present as moxifloxacin hydrochloride monohydrate.
For the preparation of moxifloxacin hydrochloride monohydrate, WO2008138759 discloses a method for preparing moxifloxacin hydrochloride monohydrate by: 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinoline carboxylic acid and S, S-2, 8-diazabicyclo [4.3.0] nonane are used as raw materials, moxifloxacin is generated by reaction in DMF or DMSO, then salified and purified with L (+) -tartaric acid (or fumaric acid or L-2-p-methylbenzoyl tartaric acid) in DMF, and finally moxifloxacin monohydrate is obtained by treatment with concentrated hydrochloric acid in a mixed solvent of ethanol and water. After analysis, the method needs chiral resolution, and the solvent DMF or DMSO used has high boiling point and difficult recovery, which is not beneficial to solvent recovery in actual industrial production, and therefore, the method is not suitable for industrial and industrialized production application.
In CN102344447, a method for preparing moxifloxacin monohydrate is described, in which moxifloxacin is first separated from moxifloxacin hydrochloride by using saturated sodium hydroxide, then moxifloxacin is converted into moxifloxacin hydrochloride monohydrate under a proper aqueous solvent or environment, but the method needs to perform "reworking" treatment on moxifloxacin hydrochloride to prepare moxifloxacin, so that the production cost is increased in no way, and therefore, the method cannot be practically used for industrial production.
Disclosure of Invention
On the basis of researching a moxifloxacin synthesis process and combining with industrial production practice, the application aims to provide a preparation method of high-yield and high-purity moxifloxacin hydrochloride monohydrate, thereby laying a certain technical foundation for the industrial preparation of the moxifloxacin hydrochloride monohydrate.
The technical scheme provided by the application is specifically introduced as follows.
A method for preparing moxifloxacin hydrochloride monohydrate, which 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, performing chelation reaction on the TF-A under the catalysis to generate TF-B (1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid-O3, O4-diacetic acid boron ester) intermediate, and then adopting Sub>A one-pot method to condense, hydrolyze, salify and remove impurities from the TF-B to obtain high-purity moxifloxacin hydrochloride monohydrate; the method specifically comprises the following steps:
(one) Synthesis of TF-B intermediate
(1) Firstly, reacting acetic anhydride, boric acid and a catalyst reaction system in a reaction container at 105-120 ℃ for 0.5-3 h (in order to ensure that the reaction is sufficient, stirring the reaction system in proper time and proper amount in the reaction process); after the reaction is finished, cooling to 30-80 ℃ for standby;
The catalyst is as follows: one or a mixture of several of Lewis acid BF3, feCl3, alCl3, znCl2 and SnCl4 in any proportion;
(2) Then, adding ethyl 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (TF-A), and reacting for 2-5 hours at 105-120 ℃ to ensure sufficient reaction (thin layer chromatography TLC can be adopted, ethyl acetate is used as developing agent for detection until TF-A raw materials disappear);
TF-Sub>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 a proper amount in time), centrifugally filtering, 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-quinoline carboxylic acid-O3, O4-diacetic acid boron ester);
The determination shows that under the above process conditions, the mass yield is: 126% -131%; 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), organic base and TF-C ((S, S) -2, 8-diazabicyclo [4,3,0] nonane) into an organic solvent (specifically acetonitrile, for example), heating, refluxing and reacting until the reaction is terminated (the reaction is terminated by adopting thin layer chromatography TLC, methanol: dichloromethane=4:1 is taken as developing agent for detection);
The organic base is as follows: one or a mixture of several of triethylamine, dipropylamine, tert-butylamine, pyridine, DMAP and DIPEA in any proportion;
(2) Then adding active carbon (2-5% of the mass ratio) for decoloring for 30-60 min, and filtering while the active carbon is hot;
(3) Then adding alkanol solvent into the filtrate, dropwise adding hydrochloric acid, and stirring for 2h after the dropwise adding;
the hydrochloric acid is hydrochloric acid with the concentration of 5-12 mol/L;
The alcohol solvent is as follows: one or a mixture of a plurality of C1-C4 alkanol solvents in any proportion;
TF-B intermediate in mass ratio: alkanol solvent = 1: (2-10);
(4) Then adding a impurity removing solvent, heating, preserving heat for 10-60 min, cooling to-10 ℃ in a gradient way, and continuously stirring for 4-6 hours;
The impurity removing solvent is as follows: one or a mixture of more than one of C1-C4 alkanol solvent, acetone, ethyl acetate, acetonitrile and THF in any proportion;
TF-B intermediate in mass ratio: impurity removal solvent = 1: (2-10);
the heating is to heat to 40-90 ℃; the aim of preserving heat for a certain time after heating is to more effectively remove impurities in a reaction system by using the impurity removing solvent;
the gradient cooling refers to cooling rate of 5-15 ℃/h;
(5) Finally, carrying out solid-liquid separation, eluting a filter cake by using a impurity-removing solvent, and drying to obtain a yellow moxifloxacin hydrochloride monohydrate finished product;
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;
The process route provided by the application uses TF-A as Sub>A starting material, and is subjected to chelation, condensation and hydrolysis to form hydrochloride, and impurity removal to prepare moxifloxacin hydrochloride monohydrate. When the process route is analyzed, compared with the existing other process routes, the preparation method of moxifloxacin hydrochloride monohydrate provided by the application has the following advantages: the adoption of the one-pot process can greatly simplify the preparation process of moxifloxacin hydrochloride; the method can realize continuous production without multiple separation and purification, thereby being beneficial to reducing the loss of raw materials and products, improving the yield, reducing and lowering the labor intensity, improving the operation production environment and lowering the industrial production cost.
In general, the preparation method provided by the application has the advantages of mild reaction conditions, easy control of the production process, batch and continuous production, no enantiomer generation in the reaction process, and no need of adding chiral resolving agent. By combining the related detection results, the product quality is high, single impurity is less than or equal to 0.05 percent (as can be seen from the HPLC detection results of the finished product, no impurity peak is more than 0.05 percent in the finished product), total impurity is less than or equal to 0.1 percent, the purity of moxifloxacin hydrochloride monohydrate is as high as more than 99.90 percent, the product stability is good, and the product can be directly used as a raw material for producing and preparing finished product medicaments, and has better production advantages.
Drawings
FIG. 1 shows the HPLC detection result of moxifloxacin hydrochloride monohydrate prepared in example 1;
FIG. 2 is an XRD spectrum of the finished moxifloxacin acid monohydrate prepared in example 1;
FIG. 3 shows the HPLC detection result of moxifloxacin hydrochloride monohydrate prepared in example 2;
FIG. 4 is an XRD pattern for the finished moxifloxacin acid monohydrate prepared in example 2;
FIG. 5 shows the HPLC detection result of moxifloxacin hydrochloride monohydrate prepared in example 3;
fig. 6 is an XRD spectrum of the finished moxifloxacin acid monohydrate prepared in example 3.
Detailed Description
The application is further illustrated by the following examples.
Example 1
Taking the specific material dosage as an example, the preparation process of moxifloxacin hydrochloride monohydrate is specifically explained as follows.
(One) Synthesis of TF-B intermediate
(1) Firstly, in a reaction vessel, 480g of acetic anhydride, 145g of boric acid and 3.5g of catalyst (anhydrous zinc chloride) are stirred and reacted for 1.5h at 110 ℃; after the reaction is finished, cooling to about 60 ℃ for standby;
(2) Subsequently, 500g of ethyl 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (TF-Sub>A) was added and reacted at 110 ℃ for 4 hours to ensure adequate reaction (thin layer chromatography TLC, detection with ethyl acetate as developing agent until TF-Sub>A starting material disappeared);
TF-Sub>A: catalyst = 1: (0.0065.+ -. 0.002);
(3) Finally, after the reaction system is naturally cooled (cooled to about 60 ℃), transferring into water, stirring and quenching for 2 hours, centrifuging and filtering, washing and drying a filter cake by using 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-diacetic acid boron ester);
weighing showed that 640.5g of yellow solid TF-B was obtained in total after drying, calculated to give a mass yield of 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, after the mixture is uniformly mixed, the temperature is raised, and the reflux reaction is carried out until the reaction is stopped (the reaction is stopped by adopting thin layer chromatography TLC, and methanol: dichloromethane=4:1 is taken as developing agent for detection);
(2) Subsequently, 2.5g of activated carbon is added for decoloration for 45min, and the mixture is filtered while hot;
(3) Then, methanol (300 g) serving as an alkanol solvent is added into the filtrate, hydrochloric acid (6 mol/L concentration) is added dropwise to adjust the pH to be 1.5, and the mixture is stirred for 2 hours after the dripping;
(4) Then adding a impurity removing solvent (400 g of acetone), heating to 40 ℃ after the adding is finished, preserving the heat for 30min, cooling to about 4 ℃ in a gradient way at a cooling rate of 8 ℃/h, and continuously stirring for 4 hours;
(5) Finally, carrying out solid-liquid separation, eluting a filter cake by using an impurity removing solvent (acetone), and drying to obtain a yellow moxifloxacin hydrochloride monohydrate finished product;
The drying mode can adopt forced air drying, the drying temperature is 50 ℃, and the drying time is 10 hours;
weighing and calculation show that the finished product of the color moxifloxacin hydrochloride monohydrate (the water content is 4.2%) is 93.5g, and the mass yield is 93.5%.
The HPLC detection result of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in fig. 1, and the purity is 99.95%.
The XRD spectrum of the finished moxifloxacin hydrochloride monohydrate product is shown in fig. 2, and it can be seen that 2θ= 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 have diffraction peaks with sharp features in the XRD spectrum, and the crystal forms are consistent with those of the original monohydrate.
Based on the above process parameters, single factor adjustment experiments were performed on part of the process parameters in the preparation process of moxifloxacin hydrochloride monohydrate, and specific test results are shown in table 1 below.
Table 1, investigation of part of the process parameters of the moxifloxacin hydrochloride monohydrate preparation
Note that: in the "crystallization temperature investigation" treatment, no gradient cooling treatment was employed, and only the result was a single temperature range treatment.
Based on the results of the table, it can be seen that the experimental process parameters after the optimization have relatively optimal preparation effects.
Example 2
The moxifloxacin hydrochloride monohydrate finished product prepared in this example is substantially the same as that in example 1, and only a part of the process parameters are adjusted, specifically:
The TF-B intermediate in step (one) was prepared as in example 1;
in the step (two):
(1) 125g of TF-B intermediate, organic base (37 g of dipropylamine) and 45g of TF-C were added to 320g of acetonitrile for reaction;
(2) Adding 3.0g of active carbon for decoloring for 50min;
(3) The alkanol solvent is 350g of methanol; hydrochloric acid is 5mol/L hydrochloric acid, and the pH value is regulated to be 1.5;
(4) 550g of acetone is adopted as the impurity removing solvent, the temperature is raised to 50 ℃, then the heat is preserved for 1h, the cooling rate is 10 ℃/h, the temperature is lowered to about 2 ℃, and the stirring is continued for 4 hours;
(5) Finally, carrying out solid-liquid separation, eluting a filter cake by using an impurity removing solvent (acetone), and drying to obtain a yellow moxifloxacin hydrochloride monohydrate finished product;
The drying mode can adopt forced air drying, the drying temperature is 50 ℃, and the drying time is 10 hours;
Weighing and calculation show that the finished product of the color moxifloxacin hydrochloride monohydrate (the water content is 4.5%) is 116.1g, and the mass yield is 92.9%.
The HPLC detection result of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in fig. 3, and the purity is 99.96%.
The XRD spectrum of the finished moxifloxacin hydrochloride monohydrate product is shown in fig. 4, and it can be seen that 2θ= 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 have diffraction peaks with sharp features in the XRD spectrum, and the crystal forms are consistent with those of the original monohydrate.
Example 3
The moxifloxacin hydrochloride monohydrate finished product prepared in this example is substantially the same as that in example 1, and only a part of the process parameters are adjusted, specifically:
The TF-B intermediate in step (one) was prepared as in example 1;
in the step (two):
(1) 200g of TF-B intermediate, organic base (41.5 g of tert-butylamine) and 70.5g of TF-C were added to 500g of acetonitrile for reaction;
(2) Adding 5.0g of active carbon for decoloring for 60min;
(3) The alkanol solvent is 620g of methanol; hydrochloric acid is 5mol/L hydrochloric acid, and the pH value is regulated to be 2.0;
(4) The impurity removing solvent adopts 900g of acetone, the temperature is raised to 60 ℃, then the heat is preserved for 1h, the cooling rate is 8 ℃/h, the temperature is lowered to about 5 ℃, and the stirring is continued for 4 hours;
(5) Finally, carrying out solid-liquid separation, eluting a filter cake by using an impurity removing solvent (acetone), and drying to obtain a yellow moxifloxacin hydrochloride monohydrate finished product;
The drying mode can adopt forced air drying, the drying temperature is 50 ℃, and the drying time is 10 hours;
weighing and calculation show that 187.5g of finished product of the color moxifloxacin hydrochloride monohydrate (the water content is 4.3%) is obtained, and the mass yield is 93.8%.
The HPLC detection result of the prepared moxifloxacin hydrochloride monohydrate finished product is shown in fig. 5, and the purity is 99.95%.
As shown in fig. 6, the XRD spectrum of the finished moxifloxacin hydrochloride monohydrate product shows that 2θ= 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 have diffraction peaks with sharp features, and the crystal forms are consistent with those of the original ground monohydrate crystal forms in comparison with the existing literature values.
Claims (6)
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, TF-A is subjected to chelation reaction under the catalysis to generate Sub>A TF-B intermediate, and then Sub>A one-pot method is adopted to obtain moxifloxacin hydrochloride monohydrate by condensation, hydrolysis, salifying and impurity removal of TF-B;
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-diacetic acid boron ester;
the preparation method specifically comprises the following steps:
(one) Synthesis of TF-B intermediate
(1) Firstly, reacting acetic anhydride, boric acid and a catalyst reaction system in a reaction container for 0.5-3 h at 105-120 ℃;
the catalyst is Lewis acid;
(2) Then adding TF-A, and reacting for 2-5 hours at 105-120 ℃ to ensure that the reaction is sufficient;
(3) Finally, after the reaction system is naturally cooled, transferring the reaction system into ice water for quenching, centrifuging and carrying out centrifugal filtration, and washing and drying a filter cake to obtain a yellow solid TF-B intermediate;
(II) one-pot method for preparing moxifloxacin hydrochloride monohydrate
(1) Firstly, adding the TF-B intermediate, organic base and TF-C obtained in the step (I) into an organic solvent, heating and refluxing until the reaction is terminated;
the TF-C is: (S, S) -2, 8-diazabicyclo [ 4.3.0 ] nonane;
The organic base is as follows: one or a mixture of several of triethylamine, dipropylamine, tert-butylamine, pyridine, DMAP and DIPEA in any proportion;
the organic solvent is acetonitrile;
(2) Then, adding activated carbon for decoloring and filtering;
(3) Then adding alkanol solvent into the filtrate, dropwise adding hydrochloric acid, and stirring for full reaction after the dropwise addition;
the alkanol solvent is methanol;
(4) Then adding a impurity removing solvent, heating, preserving heat for 10-60 min, cooling to-10 ℃ in a gradient way, and continuously stirring for 4-6 hours;
The impurity removing solvent is acetone;
the heating is to heat to 40-90 ℃;
(5) Finally, solid-liquid separation is carried out, the filter cake is leached by a impurity removing solvent, and the yellow moxifloxacin hydrochloride monohydrate finished product is obtained after drying.
2. The method for preparing moxifloxacin hydrochloride monohydrate as set forth in claim 1, wherein in the step (one), the catalyst is one or a mixture of several of BF3 and FeCl 3、AlCl3、ZnCl2、SnCl4 in lewis acid in any proportion.
3. The process for preparing moxifloxacin hydrochloride monohydrate as set forth in claim 1, wherein in the step (one), TF-Sub>A is calculated in terms of mass ratio: catalyst = 1: (0.0065.+ -. 0.002).
4. The method for preparing moxifloxacin hydrochloride monohydrate as set forth in claim 1, wherein in the second step, the hydrochloric acid is 5-12 mol/L hydrochloric acid;
TF-B intermediate in mass ratio: alkanol solvent = 1: (2-10).
5. The process for preparing moxifloxacin hydrochloride monohydrate as set forth in claim 1, wherein in the second step (ii), TF-B intermediate is prepared in terms of mass ratio: impurity removal solvent = 1: (2-10).
6. The method for preparing moxifloxacin hydrochloride monohydrate as set forth in claim 1, wherein in the second step, the temperature is raised to 40 ℃ and then the temperature is kept for 30min.
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