CN110857283B - 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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- CN110857283B CN110857283B CN201810967576.3A CN201810967576A CN110857283B CN 110857283 B CN110857283 B CN 110857283B CN 201810967576 A CN201810967576 A CN 201810967576A CN 110857283 B CN110857283 B CN 110857283B
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- 239000012535 impurity Substances 0.000 title claims abstract description 96
- 238000006114 decarboxylation reaction Methods 0.000 title claims abstract description 54
- 229940124307 fluoroquinolone Drugs 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 title claims description 54
- 229960003177 sitafloxacin Drugs 0.000 title claims description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims abstract description 12
- 229910001958 silver carbonate Inorganic materials 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 238000004440 column chromatography Methods 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 5
- WUWFMDMBOJLQIV-UHFFFAOYSA-N 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid Chemical compound C1C(N)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F WUWFMDMBOJLQIV-UHFFFAOYSA-N 0.000 claims description 4
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 claims description 4
- PWNMXPDKBYZCOO-UHFFFAOYSA-N Prulifloxacin Chemical compound C1=C2N3C(C)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N(CC1)CCN1CC=1OC(=O)OC=1C PWNMXPDKBYZCOO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical class 0.000 claims description 4
- 229960003405 ciprofloxacin Drugs 0.000 claims description 4
- QGPKADBNRMWEQR-UHFFFAOYSA-N clinafloxacin Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QGPKADBNRMWEQR-UHFFFAOYSA-N 0.000 claims description 4
- 229950001320 clinafloxacin Drugs 0.000 claims description 4
- 229960000740 enrofloxacin Drugs 0.000 claims description 4
- 229960003306 fleroxacin Drugs 0.000 claims description 4
- XBJBPGROQZJDOJ-UHFFFAOYSA-N fleroxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(CCF)C2=C1F XBJBPGROQZJDOJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960002422 lomefloxacin Drugs 0.000 claims description 4
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 claims description 4
- 229960003808 nadifloxacin Drugs 0.000 claims description 4
- JYJTVFIEFKZWCJ-UHFFFAOYSA-N nadifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)CCC3=C1N1CCC(O)CC1 JYJTVFIEFKZWCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960001180 norfloxacin Drugs 0.000 claims description 4
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 4
- 229960001224 prulifloxacin Drugs 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229960004954 sparfloxacin Drugs 0.000 claims description 4
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 claims description 4
- 229950008187 tosufloxacin Drugs 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 5
- 125000001424 substituent group Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- -1 nitro, hydroxyl Chemical group 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000000911 decarboxylating effect Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229960003376 levofloxacin Drugs 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000007660 quinolones Chemical class 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000004885 tandem mass spectrometry Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 108010054814 DNA Gyrase Proteins 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- C07D401/02—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
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 (15)
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 pharmaceutically acceptable acid salt; the fluoroquinolone decarboxylation impurity is a compound shown in a formula (I) or a pharmaceutically acceptable acid salt;
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 groups, optionallySubstituted tetrahydropyrrolyl, optionally substituted piperazinyl, or optionally substituted piperidinyl;
R4is hydrogen;
R5is hydrogen or an amino group, and the amino group,
wherein the fluoroquinolone shown in the formula (II) is norfloxacin, ciprofloxacin, enrofloxacin, lomefloxacin, nadifloxacin, fleroxacin, sparfloxacin, clinafloxacin, tosufloxacin, prulifloxacin, sitafloxacin or a sitafloxacin intermediate shown in the 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);
2. 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.
3. The preparation method according to claim 1, wherein the fluoroquinolone represented by formula (II) is a sitafloxacin intermediate represented by formula (IV) or sitafloxacin; the fluoroquinolone decarboxylation impurity shown in the formula (I) is sitafloxacin intermediate decarboxylation impurity shown in the formula (III) or sitafloxacin decarboxylation impurity shown in the formula (V);
4. the method according to any one of claims 1 to 3, wherein the mass ratio of the silver carbonate to the compound of formula (II) is 0.05:1 to 0.15: 1.
5. The preparation method according to claim 4, wherein the mass ratio of the silver carbonate to the compound of formula (II) is 0.08:1 to 0.1: 1.
6. The preparation method according to any one of claims 1 to 3, wherein the mass ratio of the acetic acid to the compound of formula (II) is 0.005:1 to 0.015: 1.
7. The preparation method according to claim 6, wherein the mass ratio of the acetic acid to the compound of formula (II) is 0.008:1 to 0.012: 1.
8. The production process according to any one of claims 1 to 3, wherein the aprotic organic solvent is one or more selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, and N, N-dimethylacetamide.
9. The method according to claim 8, wherein the aprotic organic solvent is dimethylsulfoxide.
10. The process according to any one of claims 1 to 3, wherein the volume ratio of the aprotic organic solvent to the mass of the compound of formula (II) is from 2ml/g to 10 ml/g.
11. The method according to claim 10, wherein the ratio of the volume of the aprotic organic solvent to the mass of the compound of formula (II) is 4 to 7 ml/g.
12. The method according to any one of claims 1 to 3, wherein the heating is carried out at a temperature of 100 ℃ to 150 ℃.
13. The method according to claim 12, wherein the heating is performed at a temperature of 100 ℃ to 120 ℃.
14. The method according to any one of claims 1 to 3, wherein the stirring reaction is carried out for a reaction time of 5 to 20 hr.
15. The method according to claim 14, wherein the stirring reaction is carried out for a reaction time of 10 to 15 hr.
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