CN118930482A - A preparation method of sitafloxacin impurity P-2 - Google Patents
A preparation method of sitafloxacin impurity P-2 Download PDFInfo
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- CN118930482A CN118930482A CN202410977129.1A CN202410977129A CN118930482A CN 118930482 A CN118930482 A CN 118930482A CN 202410977129 A CN202410977129 A CN 202410977129A CN 118930482 A CN118930482 A CN 118930482A
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- 239000012535 impurity Substances 0.000 title claims abstract description 74
- 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 abstract description 71
- 229960003177 sitafloxacin Drugs 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000001782 photodegradation Methods 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 22
- 229940125782 compound 2 Drugs 0.000 claims abstract description 20
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 16
- 229940125904 compound 1 Drugs 0.000 claims abstract description 11
- 239000007858 starting material Substances 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- 238000001514 detection method Methods 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229940072132 quinolone antibacterials Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- 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
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供一种西他沙星杂质P‑2的制备方法，其以化合物1为起始原料，经脱保护反应得到化合物2，再对所述化合物2进行光降解反应得到所述西他沙星杂质P‑2。本发明提供的西他沙星杂质P‑2的制备方法简单，产品纯度高。本发明提供的他沙星杂质P‑2可用于西他沙星及其片剂的有关物质检测，对西他沙星质量研究起到积极的作用。
The present invention provides a method for preparing a sitafloxacin impurity P-2, which uses compound 1 as a starting material, obtains compound 2 through a deprotection reaction, and then performs a photodegradation reaction on the compound 2 to obtain the sitafloxacin impurity P-2. The preparation method of the sitafloxacin impurity P-2 provided by the present invention is simple, and the product purity is high. The sitafloxacin impurity P-2 provided by the present invention can be used for the detection of related substances of sitafloxacin and its tablets, and plays a positive role in the quality research of sitafloxacin.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of sitafloxacin impurity P-2.
Background
Sitafloxacin (sitafloacin hydrate) was developed by the first pharmaceutical Sanco Co., ltd (Daiichi Sankyo) 1992 and was marketed for the first time in 2008 as a fourth generation quinolone antibacterial drug under the chemical name 7- [ (7S) -7-amino-5-azaspiro [2.4] hept-5-yl ] -8-chloro-6-fluoro-1- [ (1R, 2S) -cis-2-fluorocyclopropyl ] -1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid. Sitafloxacin is a novel quinolone antibacterial drug with excellent oral and broad-spectrum antibacterial properties, has strong broad-spectrum antibacterial activity on clinical isolates such as gram-negative bacteria, gram-positive bacteria, anaerobic bacteria and the like, and is used for treating severe infections of respiratory tract and urinary systems, in particular for producing severe drug resistance to common fluoroquinolone antibacterial drugs.
The structure of sitafloxacin is as follows:
The sitafloxacin itself is sensitive to humidity and illumination environment and is easy to degrade, the Japanese IF file shows that sitafloxacin photodegradation can produce impurity P-2, document "Photochemical Behavior of Sitafloxacin,Fluoroquinolone Antibiotic,in an Aqueous Solution",Tetsuya Araki,Yukinori Kawai et al describes a method for obtaining sitafloxacin impurity P-2 by photodegradation by taking sitafloxacin as a starting material, but the degraded solution obtained by photodegradation of the method has low impurity P-2 content and contains impurity P-1, and the peak positions of impurity P-1 and impurity P-2 are adjacent, so that the separation effect is poor, and the purified impurity P-2 contains impurity P-1. Therefore, the existing method for preparing the impurity P-2 has the problems of low photodegradation conversion rate, difficult separation and poor purity of the obtained impurity P-2.
When sitafloxacin is registered in China, because sitafloxacin is unstable and photodegradation products have certain toxicity, the national drug administration drug evaluation center requires detection and research on photodegradation products. In order to effectively perform the research of the development and the supplementation of sitafloxacin report data, the high-purity sitafloxacin impurity P-2 needs to be used as a reference substance for detection. However, the standard substance P-2 of sitafloxacin is mostly imported abroad, the price is high, and the ordering period is long. The purity of the sitafloxacin impurity P-2 prepared by the method for obtaining the sitafloxacin impurity P-2 by photodegradation with sitafloxacin as a starting material cannot meet the purity requirement of a reference substance.
Therefore, it is urgent and important to find a preparation method capable of obtaining high-purity sitafloxacin impurity P-2.
Disclosure of Invention
The invention aims to provide a novel method for preparing sitafloxacin impurity P-2 so as to obtain high-purity impurity P-2.
In order to solve the technical problems, the invention adopts the following technical scheme:
The invention provides a preparation method of sitafloxacin impurity P-2, which comprises the steps of taking a compound 1 as an initial raw material, carrying out deprotection reaction to obtain a compound 2, and carrying out photodegradation reaction on the compound 2 to obtain the sitafloxacin impurity P-2;
Wherein, the structural formula of the compound 1 is as follows:
the structural formula of the compound 2 is
The structural formula of the sitafloxacin impurity P-2 is
Further, the deprotection reaction is carried out in the presence of an organic solvent and an acid.
Still further, the organic solvent is dichloromethane, chloroform or ethyl acetate.
Still further, the amount of the organic solvent to be added is 10 to 20mL of the organic solvent per 1g of the compound 1. For example, 10mL, 11mL, 12mL, 13mL, 14mL, 15mL, 16mL, 17mL, 18mL, 19mL, or 20mL of the organic solvent is added per 1g of the compound 1.
Still further, the acid is hydrochloric acid with a mass concentration of 30 to 38%, for example 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37% or 38%.
Still further, the acid is fed in an amount 1 to 2 times the mass of the compound 1. For example, the acid is fed 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 times the mass of the compound 1.
Still further, the temperature of the deprotection reaction is 15 to 20℃such as 15℃16℃17℃18℃19℃or 20 ℃.
Still further, the deprotection reaction is carried out for a period of 0.1 to 1h, for example 0.1h, 0.2h, 0.3h, 0.4h, 0.5h, 0.6h, 0.7h, 0.8h, 0.9h or 1h. More preferably, the time of the deprotection reaction is 0.2 to 1 hour, still more preferably 0.3 to 1 hour.
According to some specific and preferred embodiments, the specific steps of the deprotection reaction comprise:
(1) Adding the compound 1 into an organic solvent, and stirring to dissolve;
(2) Adding acid into the reaction system in the step (1) to carry out the deprotection reaction;
(3) Adding water into the reaction system of the step (2), crystallizing, filtering, washing with water, and vacuum drying to obtain the compound 2.
Further, the photodegradation reaction is controlled to be performed in a solvent, wherein the solvent is one or more of acetonitrile, acetone, tetrahydrofuran and water.
Still further, the solvent is a mixed solvent of water and one or more of acetonitrile, acetone and tetrahydrofuran.
Further, the solvent is a mixed solvent of water and acetonitrile, a mixed solvent of water and acetone or a mixed solvent of water and tetrahydrofuran in a volume ratio of 2-3:1. For example, the volume ratio of the mixed solvent is 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, or 3:1.
Further, the pH of the reaction system of the photodegradation reaction is controlled to 3.5 to 8.5, for example, to 3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8、8.1、8.2、8.3、8.4 or 8.5.
Still further, the pH of the reaction system of the photodegradation reaction is controlled to be 4.5 to 5.
Still further, the pH of the reaction system of the photodegradation reaction is adjusted by an alkali solution.
Further, the alkali solution is 0.5-5% ammonia water.
Further, the light irradiation intensity of the photodegradation reaction is controlled to be 1400-1600 lux.
Further, the photodegradation reaction is controlled to a temperature of 10 to 30 ℃, for example, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃,16 ℃, 17 ℃,18 ℃, 19 ℃, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ or 30 ℃.
Still further, the temperature of the photodegradation reaction is controlled to be 10 to 15 ℃.
Further, the photodegradation reaction is controlled for 3 to 9 days, for example, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days or 9 days.
Still further, the photodegradation reaction is controlled to be 7 to 9 days.
According to some specific and preferred embodiments, the specific steps of the photodegradation reaction include:
(a) Adding the compound 2 into a solvent, and stirring to dissolve;
(b) Adjusting the pH of the system of step (a) with a base;
(c) And (3) exposing the system in the step (b) to light irradiation to perform the photodegradation reaction.
Further, the preparation method further comprises the step of separating and purifying the reaction system by using a preparation liquid phase instrument gradient after the photodegradation reaction is finished.
Still further, the separated and purified mobile phase is acetonitrile and water.
Still further, the gradient of the mobile phase is: 0.02,85:15, 15.0,85:15, 16.0,10:90, 26.0,10:90, 27.0,85:15, 45.0,85:15 (time, water: acetonitrile).
Still further, the amount of feed was 0.5mL.
Compared with the prior art, the invention has the following advantages:
The preparation method of sitafloxacin impurity P-2 provided by the invention is simple, and the product purity is high. The tafloxacin impurity P-2 provided by the invention can be used for detecting related substances of sitafloxacin and tablets thereof, and plays an active role in sitafloxacin quality research.
Drawings
FIG. 1 is an HPLC chart of sitafloxacin impurity P-2;
FIG. 2 is an MS diagram of sitafloxacin impurity P-2;
FIG. 3 is a 1H-NMR spectrum of sitafloxacin impurity P-2;
fig. 4 is an HPLC diagram of compound 2.
Detailed Description
The invention is further described below with reference to examples. The present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions which are not noted are conventional conditions in the industry. The technical features of the various embodiments of the present invention may be combined with each other as long as they do not collide with each other.
In the report of the published literature, the preparation method of sitafloxacin impurity P-2 is prepared by photodegradation by taking sitafloxacin as a starting material, but the preparation method has the following problems: not only has low photodegradation reaction conversion rate, but also the obtained product has poor purity and can not be used as a reference substance.
To overcome the defects, the application takes sitafloxacin intermediate (compound 1,7- [ (S) -7- [ (tert-butoxycarbonyl) amino ] -5-azaspiro [2.4] heptane-5-yl ] -6-fluoro-1- [ (1R, 2S) -2-fluorocyclopropane ] -4-oxo-1, 4-dihydro-3-quinoline carboxylic acid) as starting material, and obtains compound 2 (7- [ (S) -7-amino ] -5-azaspiro [2.4] heptane-5-yl ] -6-fluoro-1- [ (1R, 2S) -2-fluorocyclopropane ] -4-oxo-1, 4-dihydro-3-quinoline carboxylic acid) through deprotection, photodegradation is carried out, and finally effective separation is carried out to obtain high-purity sitafloxacin impurity P-2. The degradation liquid after photodegradation by the method of the application has almost no impurity P-1, thus, the impurity P-2 with high purity can be obtained by simple separation, HPLC detection is carried out on the sitafloxacin P-2 impurity prepared by the method, the purity of the product is more than or equal to 98 percent, and 1 H-NMR and MS detection is carried out on the sample, so that the molecular structure of the sitafloxacin P-2 impurity is confirmed. The sitafloxacin impurity P-2 prepared by the method can be used as an impurity reference substance and plays an important role in the research of the reinforcement of sitafloxacin declaration data.
The reaction route of the application is as follows:
In addition, the inventor takes the sitafloxacin intermediate (compound 1) as a starting raw material, and performs deprotection and photodegradation, and then effectively separates to obtain the high-purity sitafloxacin impurity P-2, thereby smoothly completing the research on the registration of sitafloxacin.
The technical scheme and technical effect of the present invention are further described below in conjunction with examples and comparative examples.
In the following examples and comparative examples, the starting materials, reagents and the like used were obtained either commercially or by self-preparation by existing methods, and for example, compound 1 can be obtained by the methods described in U.S. Pat. No. 2005/0143407A1, EP0341493 and the like. In the following examples and comparative examples, "%" means mass percent unless otherwise specified.
In the following examples and comparative examples, the HPLC detection conditions involved are as follows:
instrument: HPLC-9 Agilent
Chromatographic column: agilent C18.6X250 mm,5 μm
Mobile phase: a0.1% ammonium hydroxide (pH adjusted to 2.4 with formic acid)
Acetonitrile
A:B＝80:20
Sample injection amount: 20 μl, column temperature: 25 DEG C
Example 1
Preparation of Compound 2
5.0G of Compound 1 was added to 70ml of methylene chloride and the solution was stirred. 7.8g of 36% concentrated hydrochloric acid is added dropwise into the solution, and the mixture is stirred for 0.5h at 15-20 ℃. At the end of the reaction, 50ml of water was added, stirred for 0.5h, filtered, washed with 10ml of water, pumped down and dried under vacuum at <40℃to give compound 2 in an amount of about 4.0g with a purity of 99.0% (see FIG. 4).
Example 2
Preparation of sitafloxacin impurity P-2
2.0G of compound 2 is added into a mixed solvent of 50ml of water and 20ml of acetonitrile, the mixture is stirred and dissolved, the pH value of the system is regulated to 4.5 to 5.0 by using 1 percent ammonia water, the temperature is kept between 10 and 15 ℃, the continuous irradiation is carried out for 7 days by using 1500 lux-intensity lamplight, and the content of impurity P-2 in the degradation liquid is detected to be 17.8 percent by HPLC.
The resulting mixed solution containing impurity P-2 was separated using HPLC-17shinadzu LC-20AP (shimadzu) (column Welch Xtimate C, 21.2 x 250, 10 μm) with mobile phase gradient: 0.02,85:15, 15.0,85:15, 16.0,10:90, 26.0,10:90, 27.0,85:15, 45.0,85:15 (time, water: acetonitrile), the amount of sample introduced was 0.5ml. The preparation was collected and lyophilized to give sitafloxacin impurity P-2 310mg, purity 98.7% (see FIG. 1).
The structural identification data of impurity P-2 are as follows:
1H-NMR(400MHZ,DMSO-d6)δ：15.44(s,1H),8.70(s,2H),8.46(s,2H),7.87(d,J＝11.6Hz,1H),7.24(s,1H),7.22(s,1H),5.38(dtd,J＝64.6,5.4,3.1Hz,1H),3.75-3.90(m,3H),3.33(s,1H),1.787-2.076(m,2H),1.234-1.443(m,4H).
ESI-MS (m/z): 392.3[ M+H ] +, and the molecular weight of the sitafloxacin impurity P-2 can be deduced to be 291.3 according to the mass spectrum result, and the molecular structure theoretical value of the molecular weight corresponds to that of the sitafloxacin impurity P-2.
Example 3
Preparation of sitafloxacin impurity P-2
2.0G of compound 2 is added into a mixed solvent of 50ml of water and 20ml of acetone, the mixture is stirred and dissolved, the pH value of the system is regulated to 4.5 to 5.0 by using 1 percent ammonia water, the temperature is kept between 10 and 15 ℃, the continuous irradiation is carried out for 9 days by using 1500 lux-intensity lamplight, and the content of impurity P-2 in the degradation liquid is detected to be 12.5 percent by HPLC.
The obtained mixed solution containing the impurity P-2 is separated according to the same liquid phase preparation condition of the embodiment 2, and the sitafloxacin impurity P-2 220mg is obtained through freeze-drying, and the purity is 98.5%.
Example 4
Preparation of sitafloxacin impurity P-2
2.0G of compound 2 is added into 50ml of water, the pH value of the system is regulated to 8.0-8.5 by using 1% ammonia water, the system is stirred for dissolving, the temperature is kept at 15-20 ℃, the light with 1600lux intensity is used for irradiation for 7 days, and the content of impurity P-2 in the degradation liquid is detected to be 2.3% by HPLC.
The obtained mixed solution containing the impurity P-2 was separated under the same liquid phase preparation conditions as in example 2, and lyophilized to obtain 30mg of sitafloxacin impurity P-2 with a purity of 98.1%.
Example 5
Preparation of sitafloxacin impurity P-2
2.0G of compound 2 is added into 50ml of water, the pH value of the system is regulated to 3.5-4.0 by using 1% ammonia water, the temperature of the stirred solution is kept between 25 and 30 ℃, the light with 1600lux intensity is used for irradiation for 7 days, and the content of impurity P-2 in the degradation liquid is detected to be 1.6% by HPLC.
The obtained mixed solution containing the impurity P-2 was separated under the same liquid phase preparation conditions as in example 2, and lyophilized to obtain 15mg of sitafloxacin impurity P-2 with a purity of 98.3%.
Comparative example 1
2.0G of sitafloxacin is added into 50ml of water, the pH value of the system is regulated to 3.5-4.0 by using 1% formic acid, the system is stirred for dissolving, the temperature is kept between 10 and 15 ℃, the light with 1500lux intensity is used for continuous irradiation for 7 days, and the content of impurity P-2 in degradation liquid is detected to be 5.0% by HPLC.
The obtained mixed solution containing the impurity P-2 is separated according to the same liquid phase preparation condition of the embodiment 2, and the sitafloxacin impurity P-2 90mg is obtained through freeze-drying, and the purity is 92.7%.
The present invention has been described in detail with the purpose of enabling those skilled in the art to understand the contents of the present invention and to implement the same, but not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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