CN110857283A - Preparation method of fluoroquinolone decarboxylation impurity, sitafloxacin impurity and application - Google Patents
Preparation method of fluoroquinolone decarboxylation impurity, sitafloxacin impurity and application Download PDFInfo
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The application discloses a preparation method of fluoroquinolone decarboxylation impurities, which comprises the following steps: adding fluoroquinolone shown as a formula (II), catalyst silver carbonate and acetic acid into an aprotic organic solvent, and heating and stirring for reaction; after the reaction is finished, carrying out post-treatment and column chromatography separation to obtain fluoroquinolone decarboxylation impurities shown in the formula (I); wherein, the definition of each substituent group in the formula (I) and the formula (II) is shown in the specification. The preparation method is mild in reaction condition, environment-friendly, simple and convenient to operate, and the obtained impurities can be used for medicine quality research and have wide application prospects.
Description
Technical Field
The application belongs to the technical field of organic chemistry, and particularly relates to a preparation method of fluoroquinolone decarboxylation impurities, a sitafloxacin impurity and a preparation method and application thereof.
Background
Sitafloxacin (sitafloxacin) is a strong broad-spectrum novel fluoroquinolone antibacterial drug developed by the first three co-located Japan company after levofloxacin, the antibacterial activity of the drug on gram-positive cocci, gram-negative bacteria and anaerobic bacteria is 4-32 times of that of levofloxacin, and the drug has double inhibition effects on pneumococcal DNA gyrase and topoisomerase. The clinical test shows that the antibacterial agent has a very wide antibacterial spectrum, and particularly has very strong antibacterial activity on respiratory tract germs.
The structural formula of sitafloxacin is as follows:
disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
The decarboxylation impurities are impurities commonly existing in the synthetic process and the storage process of the fluoroquinolone antibiotics, so the research on the decarboxylation impurities and the preparation method thereof can be used for qualitative and quantitative analysis of the impurities in the production process of the fluoroquinolone, so that data support is provided for the subsequent research on the finished fluoroquinolone product, the hybrid spectrum of the fluoroquinolone is perfected, and the quality standard of the fluoroquinolone is promoted to be improved.
Marks, Kevin R.et al (Bioorganic and Medicinal Chemistry Letters,2011, vol.21, #15, p.4585-4588) and Nguyen, Son T.et al (Bioorganic and Medicinal Chemistry Letters,2011, vol.21, #19, p.5961-5963) report a process for decarboxylating decarboxylated impurities of quinolone compounds: potassium cyanide or sodium cyanide is used as a decarboxylation reagent, but cyanide is a highly toxic product and is not friendly to human bodies and the environment, so that the application of the method is limited.
Chinese patents CN105037266A and Furuta, Takayuki et al (Journal of medicinal chemistry,2006, vol.49, #7, p.2186-2192) report another decarboxylation method: diphenyl ether is used as solvent to carry out high-temperature decarboxylation, but the required temperature is higher (more than 250 ℃), and the reaction condition is harsh.
The application provides a preparation method of fluoroquinolone decarboxylation impurities, the preparation method of the impurities is not reported in fluoroquinolone compound decarboxylation preparation, the reaction conditions are mild, the operation is convenient, the environment is friendly, the application is wide, and meanwhile, severe conditions such as use of hypertoxic cyanide and high temperature can be avoided.
A first object of the present application is to provide a method for the preparation of fluoroquinolone decarboxylating impurities.
A second object of the present application is to provide sitafloxacin or its intermediate decarboxylated impurities.
A third object of the present application is to provide the use of sitafloxacin or its intermediate decarboxylated impurities.
In embodiments herein, there is provided a process for the preparation of a fluoroquinolone decarboxylated impurity, comprising the steps of:
adding fluoroquinolone, a catalyst of silver carbonate and acetic acid into an aprotic organic solvent, and heating and stirring for reaction;
after the reaction is finished, carrying out post-treatment and column chromatography separation to obtain the fluoroquinolone decarboxylation impurities;
wherein, the fluoroquinolone is a compound shown as a formula (II), or a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable acid salt thereof; the fluoroquinolone decarboxylation impurity is a compound shown as a formula (I), or a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable acid salt thereof;
a in the formula (I) and the formula (II) is C or N;
when A is C, R1Is hydrogen, unsubstituted C1-C4 alkyl, substituted C1-C4 alkyl, unsubstituted cyclopropyl, substituted cyclopropyl, unsubstituted phenyl, or substituted phenyl;
R2is hydrogen, fluorine, chlorine, bromine, unsubstituted C1-C4 alkyl, or substituted C1-C4 alkyl;
or, R1And R2Together form the following residues:
R3is hydrogen, F, chlorine, bromine, amino, one or two C1-C4 alkyl substituted amino, optionally substituted tetrahydropyrrolyl, optionally substituted piperazinyl, or optionally substituted piperidinyl;
R4is hydrogen or S, and when R4When is S, R4And R1Together form the following residues:
R5is hydrogen or amino;
when A is N, R1Is hydrogen, unsubstituted C1-C4 alkyl, substituted C1-C4 alkyl, unsubstituted cyclopropyl, substituted cyclopropyl, unsubstituted phenyl, or substituted phenyl;
R2is absent;
R3is hydrogen, F, chlorine, bromine, amino, one or two C1-C4 alkyl substituted amino, optionally substituted tetrahydropyrrolyl, optionally substituted piperazinyl, or optionally substituted piperidinyl;
R4is hydrogen;
R5is hydrogen or amino.
In an embodiment of the present application, there is provided a process for the preparation of fluoroquinolone decarboxylated impurities represented by formula (I), wherein the unsubstituted C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
in embodiments herein, there is provided a fluoroquinolone decarboxylation impurity of formula (I), wherein the substituted C1-C4 alkyl group means that one or more hydrogens of the alkyl group are substituted with one or more groups independently selected from: halogen (which may be fluorine, chlorine, bromine, or iodine), nitro, hydroxyl, and amino.
In embodiments herein, there is provided a process for the preparation of a fluoroquinolone decarboxylated impurity of formula (I) wherein the substituted cyclopropyl is one or more hydrogens on the cyclopropyl substituted with one or more groups independently selected from: halogen (which may be fluorine, chlorine, bromine, or iodine), nitro, hydroxyl, and amino.
In an embodiment of the present application, there is provided a process for the preparation of fluoroquinolone decarboxylating impurities of formula (I), wherein the substituted phenyl group is one or more hydrogens on the phenyl ring substituted with one or more groups independently selected from: halogen (which may be fluorine, chlorine, bromine, or iodine), nitro, hydroxyl, and amino.
In an embodiment of the present application, there is provided a process for the preparation of fluoroquinolone decarboxylated impurities represented by formula (I), wherein the one or two C1-C4 alkyl substituted amine groups are those wherein the hydrogen on the nitrogen atom is replaced by one or two of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
In an embodiment of the present application, there is provided a process for the preparation of fluoroquinolone decarboxylated impurities of formula (I), wherein the "optional substitution" of the optionally substituted tetrahydropyrrole, optionally substituted piperazinyl and optionally substituted piperidinyl means that the hydrogen of the tetrahydropyrrole ring, piperazine ring or piperidine ring is optionally unsubstituted or substituted with one or more of the following groups: halogen (which may be fluorine, chlorine, bromine, or iodine), nitro, hydroxy, unsubstituted C1-C4 alkyl, 2-oxo-1, 3-dioxol-4-yl, and amino.
In some embodiments of the present application, there is provided a method for preparing a fluoroquinolone decarboxylated impurity represented by formula (I), wherein the fluoroquinolone represented by formula (II) is norfloxacin, ciprofloxacin, enrofloxacin, lomefloxacin, nadifloxacin, fleroxacin, sparfloxacin, clinafloxacin, tosufloxacin, prulifloxacin, sitafloxacin, or a sitafloxacin intermediate represented by formula (IV); correspondingly, the fluoroquinolone decarboxylation impurities shown in the formula (I) are norfloxacin decarboxylation impurities, ciprofloxacin decarboxylation impurities, enrofloxacin decarboxylation impurities, lomefloxacin decarboxylation impurities, nadifloxacin decarboxylation impurities, fleroxacin decarboxylation impurities, sparfloxacin decarboxylation impurities, clinafloxacin decarboxylation impurities, tosufloxacin decarboxylation impurities, prulifloxacin decarboxylation impurities, sitafloxacin decarboxylation impurities shown in the formula (V), or sitafloxacin intermediate decarboxylation impurities shown in the formula (III);
in some embodiments of the present application, there is provided a process for the preparation of a fluoroquinolone decarboxylated impurity of formula (I), wherein the post-treatment is: after the reaction is finished, adding a sodium carbonate solution, extracting with ethyl acetate, and concentrating the organic phase under reduced pressure to obtain a crude product.
In an embodiment of the application, the application provides a preparation method of fluoroquinolone decarboxylated impurities shown as a formula (I), wherein the mass ratio of silver carbonate to the compound shown as a formula (II) is 0.05: 1-0.15: 1, and optionally 0.08: 1-0.1: 1.
In an embodiment of the application, the application provides a preparation method of fluoroquinolone decarboxylated impurities shown as a formula (I), wherein the mass ratio of acetic acid to the compound shown as a formula (II) is 0.005: 1-0.015: 1, and optionally 0.008: 1-0.012: 1.
In an embodiment of the present application, there is provided a process for the preparation of fluoroquinolone decarboxylated impurities according to formula (I), wherein the aprotic organic solvent is selected from one or more of dimethylsulfoxide, N-dimethylformamide, and N, N-dimethylacetamide, optionally dimethylsulfoxide.
In an embodiment of the present application, there is provided a process for the preparation of fluoroquinolone decarboxylated impurities of formula (I), wherein the volume ratio of the aprotic organic solvent to the mass of the compound of formula (II) is from 2ml/g to 10ml/g, optionally from 4ml/g to 7 ml/g.
In an embodiment of the present application, there is provided a method for preparing fluoroquinolone decarboxylated impurities represented by formula (I), wherein the heating is performed at a temperature of 100 ℃ to 150 ℃, optionally 100 ℃ to 120 ℃.
In an embodiment of the application, the application provides a method for preparing fluoroquinolone decarboxylated impurities shown in formula (I), wherein the reaction time of the stirring reaction is 5-20 hr, optionally 10-15 hr.
In an embodiment of the present application, there is provided a method for preparing a fluoroquinolone decarboxylated impurity represented by formula (I), wherein the fluoroquinolone decarboxylated impurity represented by formula (I) is a sitafloxacin intermediate decarboxylated impurity represented by formula (III) or a sitafloxacin decarboxylated impurity represented by formula (V), the method comprising:
adding 8-chloro-6, 7-difluoro-1- [ (1R,2S) -cis-2-fluoro-1-cyclopropyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (namely, a compound shown in a formula (IV) or sitafloxacin or a compound shown in the formula (IV)) or a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable acid salt of the sitafloxacin, catalyst silver carbonate and acetic acid into an aprotic organic solvent, and heating and stirring for reaction;
after the reaction is finished, adding a sodium carbonate solution, extracting with ethyl acetate, concentrating the organic phase under reduced pressure to obtain a crude product, and separating the crude product by column chromatography to obtain the sitafloxacin intermediate decarboxylation impurity (namely the compound of the formula (III)) or the sitafloxacin decarboxylation impurity (namely the compound of the formula (V)).
In an embodiment of the application, the preparation method of sitafloxacin or intermediate decarboxylation impurities thereof is provided, wherein the mass ratio of the added silver carbonate to the compound of formula (IV) or sitafloxacin is 0.05: 1-0.15: 1, optionally 0.08: 1-0.1: 1.
In an embodiment of the application, the preparation method of sitafloxacin or intermediate decarboxylated impurities thereof is provided, wherein the mass ratio of the added amount of acetic acid to the compound of formula (IV) or sitafloxacin is 0.005: 1-0.015: 1, optionally 0.008: 1-0.012: 1.
In embodiments of the present application, there is provided a process for the preparation of sitafloxacin or its intermediate decarboxylated impurities, wherein the aprotic organic solvent is selected from one or more of dimethylsulfoxide, N-dimethylformamide, and N, N-dimethylacetamide, optionally dimethylsulfoxide.
In an embodiment of the present application, there is provided a method for preparing sitafloxacin or its intermediate decarboxylated impurities, wherein the ratio of the volume of the aprotic organic solvent to the mass of the compound of formula (IV), or sitafloxacin, is 2ml/g to 10ml/g, preferably 4ml/g to 7 ml/g.
In the embodiments of the present application, the present application provides a method for preparing sitafloxacin or decarboxylated impurities of intermediate thereof, wherein the heating means heating to a temperature of 100 ℃ to 150 ℃, preferably 100 ℃ to 120 ℃.
In an embodiment of the present application, the method for preparing sitafloxacin or its intermediate decarboxylated impurities, provided by the present application, wherein the reaction time of the stirring reaction is 5-20 hr, preferably 10-15 hr.
In another aspect, the present application provides a sitafloxacin decarboxylation impurity as shown in formula (III), or a sitafloxacin decarboxylation impurity as shown in formula (V):
in a third aspect, the application provides an application of the decarboxylated impurity of sitafloxacin intermediate shown in formula (III) or the decarboxylated impurity of sitafloxacin shown in formula (V) as a reference substance in quality research of sitafloxacin intermediate, bulk drug or sitafloxacin preparation.
The beneficial effect of this application is as follows:
(1) the application provides a preparation method of novel decarboxylation impurities of quinolone compounds, which has mild reaction conditions and simple and convenient operation, can avoid severe conditions such as use of hypertoxic cyanide and high temperature, and can be widely applied.
(2) The method can quickly obtain sitafloxacin or decarboxylation impurities of the intermediate of sitafloxacin, and has important significance in effectively controlling the quality of the sitafloxacin intermediate, the bulk drug and the preparation.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. The objectives and other advantages of the application may be realized and attained by the structure particularly pointed out in the written description and claims hereof.
Detailed Description
Hereinafter, embodiments of the present application will be described in detail to make objects, technical solutions and advantages of the present application more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
The foregoing and other aspects of the present application will become more apparent from the following detailed description, which proceeds with reference to the accompanying examples. It should not be understood that the scope of the present application is limited to the following examples, and that any technique described in the present application may be used to implement the present application.
The 8-chloro-6, 7-difluoro-1- [ (1R,2S) -cis-2-fluoro-1-cyclopropyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (compound of formula (IV)) used in the examples was prepared by a method reported in chenwu et al [ journal of chinese medical industry, 2014, 45(1) ].
EXAMPLE 1 preparation of decarboxylated impurities of sitafloxacin intermediate of formula (III)
8-chloro-6, 7-difluoro-1- [ (1R,2S) -cis-2-fluoro-1-cyclopropyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (4g), a catalyst of silver carbonate (0.35g) and acetic acid (0.038g) were added to dimethyl sulfoxide (20ml), heated to 110 ℃ and stirred to react for 12 hours. After the reaction is finished, adding a sodium carbonate solution, extracting with ethyl acetate (20ml multiplied by 3), concentrating the organic phase under reduced pressure to obtain a crude product, and separating the crude product by column chromatography (ethyl acetate: petroleum ether ═ 1:1) to obtain 2.9g of the decarboxylated impurity of the sitafloxacin intermediate, wherein the yield is 84.2%.
Example 2 preparation of decarboxylated impurities of sitafloxacin intermediate of formula (III)
8-chloro-6, 7-difluoro-1- [ (1R,2S) -cis-2-fluoro-1-cyclopropyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (4g), catalyst silver carbonate (0.32g) and acetic acid (0.032g) were added to dimethyl sulfoxide (20ml), heated to 120 ℃ and stirred to react for 15 hr. After the reaction is finished, adding a sodium carbonate solution, extracting with ethyl acetate (20ml multiplied by 3), concentrating the organic phase under reduced pressure to obtain a crude product, and separating the crude product by column chromatography (ethyl acetate: petroleum ether ═ 1:1) to obtain 2.8g of the decarboxylated impurity of the sitafloxacin intermediate, wherein the yield is 81.3%.
Example 3 preparation of decarboxylated impurities of sitafloxacin intermediate of formula (III)
8-chloro-6, 7-difluoro-1- [ (1R,2S) -cis-2-fluoro-1-cyclopropyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (4g), a catalyst of silver carbonate (0.4g) and acetic acid (0.04g) were added to dimethyl sulfoxide (25ml), and the mixture was heated to 100 ℃ and stirred to react for 10 hours. After the reaction is finished, adding a sodium carbonate solution, extracting with ethyl acetate (20ml multiplied by 3), concentrating the organic phase under reduced pressure to obtain a crude product, and separating the crude product by column chromatography (ethyl acetate: petroleum ether ═ 1:1) to obtain 2.8g of the decarboxylated impurity of the sitafloxacin intermediate, wherein the yield is 81.3%.
Example 4 confirmation of decarboxylated impurity structure of sitafloxacin intermediate shown in formula (III)
Nuclear magnetic resonance spectroscopy (BRUKER AV-300 type nuclear magnetic resonance apparatus, DMSO-d6)
1H-NMRδ(ppm):8.06(2H,m),6.15(1H,d),5.12/4.95(1H,m),4.10(1H,m),1.59(2H,m).
13C-NMRδ(ppm):174.30,151.08,148.60,147.91,145.44,136.89,124.27,111.53,108.98,74.72,72.51,16.41.
Mass spectrum (Agilent 1200-6100LC-MS/MS combination instrument)
274.1[M+H]+，296.0[M+Na]+. The molecular weight of the sample was deduced from the mass spectrometry results to be 273, consistent with the structure theory molecular weight. The molecular weight is odd, which is consistent with the odd number of N contained in the molecule of the product.
EXAMPLE 5 preparation of decarboxylated impurities of sitafloxacin of formula (V)
8-chloro-6, 7-difluoro-1- [ (1R,2S) -cis-2-fluoro-1-cyclopropyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (1g), catalyst silver carbonate (0.09g) and acetic acid (0.01g) were added to dimethyl sulfoxide (5ml), heated to 115 ℃ and reacted with stirring for 15 hr. After the reaction is finished, adding a sodium carbonate solution, extracting with ethyl acetate (6ml multiplied by 3), concentrating the organic phase under reduced pressure to obtain a crude product, and separating the crude product by column chromatography (ethyl acetate: petroleum ether ═ 2:1) to obtain 0.68g of sitafloxacin decarboxylation impurity.
Example 6 confirmation of decarboxylated impurity structure of sitafloxacin having formula (V)
Nuclear magnetic resonance spectroscopy (BRUKER AV-300 type nuclear magnetic resonance apparatus, DMSO-d6)
1H-NMRδ(ppm):8.22(2H,s),7.97/7.95(1H,m),7.75/7.71(1H,d),6.07/6.05(1H,d),5.09/4.93(1H,m),4.25(1H,m),4.05(2H,m),4.05(2H,m)3.55(1H,m),3.50(1H,m),3.19(1H,d),1.50(1H,m),1.50(1H,m),1.27(1H,m),1.21(1H,m),1.11(1H,m),0.84(2H,m).
13C-NMRδ(ppm):174.54,154.73/152.26,148.41,139.15/139.02,138.53,122.80/122.74,117.60/117.48,110.18/109.95,108.58,74.65/72.44,56.28,56.21,55.74,24.71,15.77,15.67,14.10,5.40.
Mass spectrum (Agilent 1200-6100LC-MS/MS combination instrument)
366.0[M+H]+The molecular weight of the sample was deduced from the mass spectrometry results to be 365, consistent with the structure theory molecular weight. The molecular weight is odd, which is consistent with the odd number of N contained in the molecule of the product.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.
Claims (12)
1. A preparation method of fluoroquinolone decarboxylated impurities comprises the following steps:
adding fluoroquinolone, a catalyst of silver carbonate and acetic acid into an aprotic organic solvent, and heating and stirring for reaction;
after the reaction is finished, carrying out post-treatment and column chromatography separation to obtain the fluoroquinolone decarboxylation impurities;
wherein, the fluoroquinolone is a compound shown as a formula (II), or a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable acid salt thereof; the fluoroquinolone decarboxylation impurity is a compound shown as a formula (I), or a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable acid salt thereof;
a in the formula (I) and the formula (II) is C or N;
when A is C, R1Is hydrogen, unsubstituted C1-C4 alkyl, substituted C1-C4 alkyl, unsubstituted cyclopropyl, substituted cyclopropyl, unsubstituted phenyl, or substituted phenyl;
R2is hydrogen, fluorine, chlorine, bromine, unsubstituted C1-C4 alkyl, or substituted C1-C4 alkyl;
or, R1And R2Together form the following residues:
R3is hydrogen, F, chlorine, bromine, amino, one or two C1-C4 alkyl substituted amino, optionally substituted tetrahydropyrrolyl, optionally substituted piperazinyl, or optionally substituted piperidinyl;
R4is hydrogen or S, and when R4When is S, R4And R1Together form the following residues:
R5is hydrogen or amino;
when A is N, R1Is hydrogen, unsubstituted C1-C4 alkyl, substituted C1-C4 alkyl, unsubstituted cyclopropyl, substituted cyclopropyl, unsubstituted phenyl, or substituted phenyl;
R2is absent;
R3is hydrogen, F, chlorine, bromine, amino, one or two C1-C4 alkyl substituted amino, optionally substituted tetrahydropyrrolyl, optionally substituted piperazinyl, or optionally substituted piperidinyl;
R4is hydrogen;
R5is hydrogen or amino.
2. The production process according to claim 1, wherein the fluoroquinolone represented by formula (II) is norfloxacin, ciprofloxacin, enrofloxacin, lomefloxacin, nadifloxacin, fleroxacin, sparfloxacin, clinafloxacin, tosufloxacin, prulifloxacin, sitafloxacin, or a sitafloxacin intermediate represented by formula (IV); correspondingly, the fluoroquinolone decarboxylation impurities shown in the formula (I) are norfloxacin decarboxylation impurities, ciprofloxacin decarboxylation impurities, enrofloxacin decarboxylation impurities, lomefloxacin decarboxylation impurities, nadifloxacin decarboxylation impurities, fleroxacin decarboxylation impurities, sparfloxacin decarboxylation impurities, clinafloxacin decarboxylation impurities, tosufloxacin decarboxylation impurities, prulifloxacin decarboxylation impurities, sitafloxacin decarboxylation impurities shown in the formula (V), or sitafloxacin intermediate decarboxylation impurities shown in the formula (III);
3. the production method according to claim 1, wherein the post-treatment is: after the reaction is finished, adding a sodium carbonate solution, extracting with ethyl acetate, and concentrating the organic phase under reduced pressure to obtain a crude product.
4. The preparation method according to claim 1, wherein the fluoroquinolone represented by the formula (II) is sitafloxacin intermediate represented by the formula (IV) or sitafloxacin; the fluoroquinolone decarboxylation impurity shown in the formula (I) is sitafloxacin intermediate decarboxylation impurity shown in a formula (III) or sitafloxacin decarboxylation impurity shown in a formula (V);
5. the process according to any one of claims 1 to 4, wherein the mass ratio of silver carbonate to the compound of formula (II) is from 0.05:1 to 0.15:1, optionally from 0.08:1 to 0.1: 1.
6. The preparation method according to any one of claims 1 to 4, wherein the mass ratio of acetic acid to the compound of formula (II) is 0.005:1 to 0.015:1, optionally 0.008:1 to 0.012: 1.
7. The process according to any one of claims 1 to 4, wherein the aprotic organic solvent is selected from one or more of dimethylsulfoxide, N-dimethylformamide, and N, N-dimethylacetamide, optionally dimethylsulfoxide.
8. The process according to any one of claims 1 to 4, wherein the volume of aprotic organic solvent to mass of compound of formula (II) is in the range of 2 to 10ml/g, optionally 4 to 7 ml/g.
9. The method of any one of claims 1 to 4, wherein the heating is to a temperature of from 100 ℃ to 150 ℃, optionally from 100 ℃ to 120 ℃.
10. The process according to any one of claims 1 to 4, wherein the stirring reaction is carried out for a reaction time of 5 to 20hr, optionally 10 to 15 hr.
11. The decarboxylated impurity of sitafloxacin intermediate shown in formula (III), or the decarboxylated impurity of sitafloxacin shown in formula (V):
12. the use of the decarboxylated sitafloxacin intermediate impurity of claim 11, or the decarboxylated sitafloxacin impurity as a control in the quality study of a sitafloxacin intermediate, a bulk drug or a sitafloxacin preparation.
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| CN112961153A (en) * | 2020-07-06 | 2021-06-15 | 北京新康哌森医药科技有限公司 | Preparation method of moxifloxacin impurity |
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| CN106349218A (en) * | 2016-08-25 | 2017-01-25 | 山东齐都药业有限公司 | Method for preparing sitafloxacin |
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| CN106349218A (en) * | 2016-08-25 | 2017-01-25 | 山东齐都药业有限公司 | Method for preparing sitafloxacin |
Non-Patent Citations (1)
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| YOUICHI KIMURA等: "(Fluorocyclopropyl)quinolones. 2.Synthesis and Stereochemical Structure-Activity Relationships of Chiral 7-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-l-(2-fluorocyclopropyl)quinolone Antibacterial Agents", 《J. MED. CHEM.》 * |
Cited By (2)
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|---|---|---|---|---|
| CN112961153A (en) * | 2020-07-06 | 2021-06-15 | 北京新康哌森医药科技有限公司 | Preparation method of moxifloxacin impurity |
| CN112961153B (en) * | 2020-07-06 | 2021-12-10 | 北京新康哌森医药科技有限公司 | Preparation method of moxifloxacin impurity |
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