CN114031607B - Refining method of delafloxacin and intermediate thereof - Google Patents
Refining method of delafloxacin and intermediate thereof Download PDFInfo
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- DYDCPNMLZGFQTM-UHFFFAOYSA-N delafloxacin Chemical compound C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 title claims abstract description 60
- 229950006412 delafloxacin Drugs 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000007670 refining Methods 0.000 title description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 239000002253 acid Substances 0.000 claims abstract description 17
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- 238000006460 hydrolysis reaction Methods 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 9
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 9
- 235000015165 citric acid Nutrition 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 25
- 239000000539 dimer Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 235000010265 sodium sulphite Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000005660 chlorination reaction Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229940124350 antibacterial drug Drugs 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- AHJGUEMIZPMAMR-WZTVWXICSA-N 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxoquinoline-3-carboxylic acid;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F AHJGUEMIZPMAMR-WZTVWXICSA-N 0.000 description 1
- AKAMNXFLKYKFOJ-UHFFFAOYSA-N 2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1F AKAMNXFLKYKFOJ-UHFFFAOYSA-N 0.000 description 1
- KBESHLYCSZINAJ-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(Cl)=C1F KBESHLYCSZINAJ-UHFFFAOYSA-N 0.000 description 1
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- -1 delafloxacin compound Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
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- 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
- C07D401/14—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 three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of medicine synthesis, and particularly relates to a compound preparationThe method is characterized in that a compound shown as a formula A-6 reacts with mixed acid of a chlorinating agent and sulfuric acid to obtain an intermediate compound shown as a formula A-7. The technical scheme of the invention can effectively avoid the generation of dimer impurities of delafloxacin and obtain the delafloxacin with ultrahigh purity and high yield. The purity of the delafloxacin can reach more than 99.6 percent, and the delafloxacin is more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly provides a refining method of delafloxacin and an intermediate thereof, wherein a mixed acid of sulfuric acid is used as a reaction reagent.
Background
The chemical name of delafloxacin is: 1- (6-amino-3, 5-difluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-hydroxyazetidin-1-yl) -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, having the formula 1, the corresponding meglumine salt thereof having the formula 2:
delafloxacin, the latest generation of broad-spectrum fluoroquinolone antibacterial drugs, was first developed by Wakunaga pharmaceutical company, japan, later granted for development by Melinta pharmaceutical company, usa, and approved for marketing by FDA, usa, 6 and 19 days 2017. It is mainly used for treating acute bacterial skin and skin structure infection caused by susceptible bacteria. Compared with other fluoroquinolones antibacterial drugs, delafloxacin has more excellent gram-positive bacteria resistance activity, and particularly has methicillin-resistant staphylococcus aureus resistance to other quinolone antibacterial drugs. In addition, delafloxacin can keep the activity under the acidic condition, and the characteristic can more effectively eliminate staphylococcus aureus in the acidic environment, thereby playing an important role in treating skin infection, respiratory tract infection, urinary system infection and the like.
For the synthesis of delafloxacin, there are currently two main approaches:
the first method (WO 1997011068A 1):
the delafloxacin is obtained by taking 3-chloro-2, 4, 5-trifluorobenzoic acid as an initial material through multi-step reaction by Wakunaga pharmaceutical company of Japan, but the initial material is high in price and is not easy to purchase, and excessive impurities are generated through high-temperature cyclization and high-temperature hydrolysis in the reaction synthesis step, so that the product purity is reduced, and the delafloxacin is not suitable for industrial production.
Second method (WO 2006015194 A2):
the method is synthesized by the Abbott pharmaceutical company of the U.S. Pat. No. 2,4,5-trifluorobenzoic acid as a starting material through a reaction, wherein the critical step, namely the penultimate chlorination reaction, causes the increase of impurities, and the subsequent hydrolysis reaction reaches 50 ℃, and the product impurities are increased due to the high temperature, so that the purity of the product is reduced. More unfortunately, after the delafloxacin product is separated after the reaction is completed, an impurity with an area as high as 0.43 percent appears at a relative retention time of 1.60 by HPLC, and the impurity is difficult to remove in the final salt-forming reaction, so that the delafloxacin meglumine synthesized by the method cannot reach the medicinal grade. This Impurity was identified in Hanselmann, R. et al, the < < Identification and Suppression of a Dimer injection in the Development of Delafloxacin > >, organic Process Research & Development, vol.13, pages 54-59 (2009), which was experimentally verified to be identified as a Dimer of Delafloxacin having the formula shown in FIG. 3:
it is pointed out in this context that the main cause of the impurity is the opening of the azetidine ring in the compound of formula a-7 due to the use of a sulphuric acid reagent in the chlorination reaction, which in turn produces the impurity after the completion of the latter hydrolysis reaction.
CN102164912B discloses a process for preparing delafloxacin compound, and the content of delafloxacin dimer impurity generated therein is lower than 0.40%. Although this method allows effective control of the amount of delafloxacin dimer impurity, it is still not suitable for scale-up of industrial production, and therefore, a more optimized method is sought to drastically reduce the production of the dimer impurity, further improving the purity of the product.
Disclosure of Invention
The invention aims to provide a method for preparing delafloxacin and an intermediate thereof, which can completely inhibit the generation of dimer impurities of the delafloxacin during large-scale production, obtain the delafloxacin with ultrahigh purity and high yield, meet the requirement of medicinal use and are suitable for large-scale industrial production.
In view of the above-mentioned cause of the production of delafloxacin dimer impurity, the present inventors attempted to study the chlorination reaction step and the hydrolysis reaction step of forming delafloxacin from the compound of formula a-6. The inventors have surprisingly found that when a mixed acid of sulfuric acid is used as a reagent for chlorination reaction, the production of delafloxacin dimer impurity can be completely avoided and finally ultra-high purity high yield delafloxacin is obtained.
To achieve the object of the present invention, there is provided a process for preparing a compound of formula a-7:
reacting the compound of the formula A-6 with mixed acid of a chlorinating agent and sulfuric acid to obtain a compound of a formula A-7,
the reaction formula is shown as the following formula:
preferably, the chlorinating agent is N-chlorosuccinimide.
Preferably, the mixed acid of the sulfuric acid is a mixed acid of sulfuric acid and an organic acid, the organic acid is one or more selected from citric acid, picric acid, malic acid, oxalic acid and tartaric acid, and the mixed acid of sulfuric acid and citric acid is preferred. For example, the mixed acid of sulfuric acid and citric acid is prepared by mixing sulfuric acid and citric acid in a methyl acetate solution at room temperature.
Preferably, the molar ratio of the chlorinating reagent to the compound of formula a-6 is (1-2): 1, further preferably, the molar ratio of the compound of formula a-6 is (1.16-1.20): 1, more preferably, the molar ratio of the compounds of formula a-6 is 1.18.
Preferably, the molar ratio of the mixed acid of the sulfuric acid to the intermediate I is (0.005-0.1): 1, further preferably (0.01 to 0.05): 1, more preferably (0.016-0.02): 1; wherein the molar ratio of sulfuric acid to the organic acid is 2 or more, and more preferably 3.
Preferably, the reaction solvent is selected from the group consisting of dimethyl sulfoxide, ethanol, methanol, tetrahydrofuran, dichloroethane, ethyl acetate, methyl acetate, acetonitrile, acetone, n-heptane, n-hexane, and a combination of two or more thereof, and more preferably ethyl acetate.
Preferably, the reaction temperature is controlled to be 10-35 ℃.
Further, the compound of formula a-7 undergoes a hydrolysis reaction to obtain a compound of formula 1, wherein the reaction formula is shown as follows:
the hydrolysis reaction uses hydroxide base as hydrolysis reagent, wherein the hydroxide base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide and a combination of two or more of them, preferably potassium hydroxide.
The temperature of the hydrolysis reaction is controlled to be 10-35 ℃.
Further, the invention provides a detection method of delafloxacin, which comprises the following steps:
performing high performance liquid chromatography with octadecylsilane chemically bonded silica as filler; the mobile phase A is 80% methanol acetonitrile solution, the mobile phase B is 50mM ammonium acetate solution, the detection wavelength is 290nm, the flow rate is 0.5ml per minute, the column temperature is 30 ℃, and gradient elution is carried out according to the following table 1:
TABLE 1
| Time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 35 | 65 |
| 17 | 38 | 62 |
| 20 | 40 | 60 |
| 30 | 50 | 50 |
| 49 | 65 | 35 |
| 55 | 90 | 10 |
| 60 | 35 | 65 |
According to the HPLC detection method provided above, the finally synthesized delafloxacin is used as a test sample, and the content of delafloxacin and the content of impurities such as delafloxacin dimer can be detected.
The invention has the advantages of
Compared with the existing refining method of delafloxacin, the technical scheme of the invention can thoroughly avoid the generation of dimer impurities of delafloxacin. In addition, the hydrolysis reaction temperature for generating the delafloxacin by the compound in the formula A-7 is 10-35 ℃, and is milder under the condition of obtaining the same effect compared with the hydrolysis reaction temperature in the existing delafloxacin synthesis method which is higher than 50 ℃, so that the process operation is facilitated, the generation of impurities is further reduced, the delafloxacin with ultrahigh purity and high yield is obtained through reaction, the purity of the delafloxacin can reach more than 99.6%, and the delafloxacin is more suitable for industrial amplification production.
Drawings
Figure 1 shows the HPLC mapping of the delafloxacin dimer impurity.
Figure 2 shows the HPLC detection profile of delafloxacin prepared in commercial scale quantities.
Detailed Description
For better understanding of the technical solutions of the present invention, the technical solutions of the present invention are further described below with reference to specific examples, which are only for the purpose of facilitating understanding of the present invention and should not be construed as specifically limiting the present invention.
Example 1 preparation of delafloxacin
A1L reaction flask was charged with 50.0g of the compound of formula A-6 and 150ml of ethyl acetate, and the temperature was controlled at 10-35 ℃. The NCS solution (prepared by adding 15.6g of NCS to a mixed solution of 0.13g of sulfuric acid and 0.09g of citric acid in 250ml of methyl acetate) was added dropwise, and after reaction for 6 to 10 hours after completion of the addition, the separated liquid was washed with 250g of a 1.5% aqueous sodium bicarbonate solution and 140g of a 10% aqueous sodium sulfite solution, respectively, and the solvent was evaporated in vacuo to give 51.0g of the compound of formula A-7 in a yield of 95.7%. Then 30g of the compound shown in the formula A-7, 240g of isopropanol and a potassium hydroxide aqueous solution (9.1 g of potassium hydroxide is dissolved in 225g of water) are added into a reaction bottle, the temperature is controlled to be 10-35 ℃, after 3 hours of reaction, 143g of a 12% acetic acid solution is added, after stirring for 1 hour, 23.7g of delafloxacin is obtained through suction filtration and drying, the yield is 96.1%, the purity is 99.9%, and delafloxacin dimer impurities are not detected.
Example 2 preparation of delafloxacin
A1L reaction flask was charged with 50.0g of the compound of formula A-6 and 150ml of ethyl acetate, and the temperature was controlled at 10-35 ℃. The NCS solution (prepared by adding 15.6g of NCS to a mixed solution of 0.04g of sulfuric acid and 0.26g of citric acid in 250ml of methyl acetate) was added dropwise, and after reaction for 6 to 10 hours after the addition, the resulting solution was washed with 250g of a 1.5% aqueous sodium bicarbonate solution and 140g of a 10% aqueous sodium sulfite solution, and the solvent was evaporated in vacuo to give 49.6g of the compound of formula A-7 in a yield of 93%. Then 30g of the compound shown in the formula A-7, 240g of isopropanol and a potassium hydroxide aqueous solution (9.1 g of potassium hydroxide is dissolved in 225g of water) are added into a reaction bottle, the temperature is controlled to be 10-35 ℃, after reaction is carried out for 3h, 143g of a 12% acetic acid solution is added, after stirring for 1h, suction filtration and drying are carried out to obtain 22.1g of delafloxacin, the yield is 89.8%, the purity is 99.0%, and no delafloxacin dimer impurity is detected.
Example 3 preparation of delafloxacin
A1L reaction flask was charged with 50.0g of the compound of formula A-6 and 150ml of ethyl acetate, and the temperature was controlled at 10-35 ℃. The NCS solution was added dropwise (this was done by adding 15.6g of NCS to a mixed solution of 0.34g of citric acid and 250ml of methyl acetate), and after completion of the addition and reaction for 6 to 10 hours, the resulting solution was washed with 250g of a 1.5% aqueous sodium bicarbonate solution and 140g of a 10% aqueous sodium sulfite solution, respectively, and the solvent was evaporated in vacuo to give 48.5g of the compound of formula A-7, with a yield of 91.0%. Then 30g of the compound shown in the formula A-7, 240g of isopropanol and a potassium hydroxide aqueous solution (9.1 g of potassium hydroxide is dissolved in 225g of water) are added into a reaction bottle, the temperature is controlled to be 10-35 ℃, after reaction is carried out for 3h, 143g of a 12% acetic acid solution is added, stirring is carried out for 1h, and then suction filtration and drying are carried out to obtain 20.0g of delafloxacin, wherein the yield is 81.1%, and the purity is 92.1%.
Example 4 preparation of delafloxacin
A1L reaction flask was charged with 50.0g of the compound of formula A-6 and 150ml of ethyl acetate, and the temperature was controlled at 10-35 ℃. The NCS solution (prepared by adding 15.6g of NCS to a mixed solution of 0.13g of sulfuric acid and 0.07g of tartaric acid in 250ml of methyl acetate) was added dropwise, and after completion of the addition and reaction for 6 to 10 hours, the resulting mixture was washed with 250g of a 1.5% aqueous sodium bicarbonate solution and 140g of a 10% aqueous sodium sulfite solution, and the solvent was evaporated in vacuo to give 49.6g of the compound of formula A-7 in a yield of 93%. Then 30g of the compound shown in the formula A-7, 240g of isopropanol and a potassium hydroxide aqueous solution (9.1 g of potassium hydroxide is dissolved in 225g of water) are added into a reaction bottle, the temperature is controlled to be 10-35 ℃, after reaction is carried out for 3h, 143g of a 12% acetic acid solution is added, after stirring for 1h, suction filtration and drying are carried out to obtain 22.5g of delafloxacin, the yield is 91.6%, the purity is 98.8%, and no delafloxacin dimer impurity is detected.
Example 5, preparation of delafloxacin, dosage on a commercial scale, i.e. above the kg scale.
50kg of the compound of formula A-6 and 150L of ethyl acetate are placed in a 1000L reaction flask, and the temperature is controlled at 10-35 ℃. The NCS solution was added dropwise (by adding 15.6kg of NCS to a mixed solution of 130g of sulfuric acid and 90g of citric acid in 250L of methyl acetate), and after reaction for 6 to 10 hours after completion of the addition, the resulting solution was washed with 250kg of a 1.5% aqueous sodium bicarbonate solution and 140kg of a 10% aqueous sodium sulfite solution, respectively, and the solvent was evaporated in vacuo to give 50.5kg of the compound of formula A-7 in a yield of 94.6%. Then 30kg of the compound of the formula A-7, 240kg of isopropanol and a potassium hydroxide aqueous solution (9.1 kg of potassium hydroxide is dissolved in 225kg of water) are added into a reaction bottle, the temperature is controlled at 10-35 ℃ to react for 3h, then 143kg of 12% acetic acid solution is added, stirring is carried out for 1h, suction filtration and drying are carried out to obtain 23.9kg of delafloxacin, the yield is 96.9%, the purity is 99.6%, and delafloxacin dimer impurities are not detected. The HPLC positioning spectrum of the delafloxacin dimer impurity is shown in figure 1, and the corresponding spectrum data are shown in the following table 2; the HPLC detection spectrum of the prepared delafloxacin is shown in figure 2, and the corresponding spectrum data are shown in the following table 3.
TABLE 2
TABLE 3
Comparative example 1 preparation of delafloxacin to a 1L reaction flask were added 50.0g of the compound of formula A-6 and 150ml of ethyl acetate, and the temperature was controlled at 10-35 ℃. The NCS solution was added dropwise (this was done by adding 15.6g of NCS to a mixed solution of 0.17g of sulfuric acid and 250ml of methyl acetate), and after completion of the addition and reaction for 6 to 10 hours, the resulting solution was washed with 250g of a 1.5% aqueous sodium bicarbonate solution and 140g of a 10% aqueous sodium sulfite solution, respectively, and the solvent was evaporated in vacuo to give 46.1g of the compound of formula A-7, with a yield of 86.3%. Then 30g of the compound of the formula A-7, 240g of isopropanol and a potassium hydroxide aqueous solution (9.1 g of potassium hydroxide is dissolved in 225g of water) are added into a reaction bottle, the temperature is controlled to be 10-35 ℃, after 3 hours of reaction, 143g of a 12% acetic acid solution is added, after stirring for 1 hour, 22.1g of delafloxacin is obtained by suction filtration and drying, the yield is 89.7%, the purity is 94.2%, and 0.3% of delafloxacin dimer impurity is detected.
Claims (16)
1. A method for preparing delafloxacin intermediate compound shown as formula (A-7) is characterized in that the compound shown as formula (A-6) is reacted with mixed acid of chlorinating agent and sulfuric acid to obtain the compound shown as formula (A-7), wherein the reaction formula is shown as the following formula:
wherein the mixed acid of the sulfuric acid is the mixed acid of the sulfuric acid and an organic acid, and the organic acid is one or more acids selected from citric acid, malic acid, oxalic acid and tartaric acid.
2. The method of claim 1, wherein the chlorinating reagent is N-chlorosuccinimide.
3. The production process according to claim 1, wherein the molar ratio of sulfuric acid to organic acid in the mixed acid of sulfuric acid is 2 or more.
4. The production method according to claim 1, wherein the molar ratio of the chlorinating reagent to the compound of formula (a-6) is (1-2): 1.
5. the production method according to claim 4, wherein the molar ratio of the chlorinating reagent to the compound of formula (A-6) is (1.16-1.20): 1.
6. the production method according to claim 4, wherein the molar ratio of the chlorinating reagent to the compound of formula (A-6) is 1.18.
7. The production method according to claim 1, wherein the molar ratio of the mixed acid of sulfuric acid to the compound of the formula (a-6) is (0.005-0.1): 1.
8. the production method according to claim 7, wherein the molar ratio of the mixed acid of sulfuric acid to the compound of formula (A-6) is (0.01-0.05): 1.
9. the production method according to claim 7, wherein the molar ratio of the mixed acid of sulfuric acid to the compound of the formula (A-6) is (0.016 to 0.02): 1.
10. the method according to claim 1, wherein the reaction solvent is selected from the group consisting of dimethyl sulfoxide, ethanol, methanol, tetrahydrofuran, dichloroethane, ethyl acetate, methyl acetate, acetonitrile, acetone, n-heptane, n-hexane and a combination of two or more thereof.
11. The method of claim 10, wherein the solvent is ethyl acetate.
12. The method according to claim 1, wherein the reaction temperature is controlled to 10 to 35 ℃.
13. The preparation method according to claim 1, further comprising subjecting the compound of formula (A-7) to hydrolysis reaction to obtain the compound of formula (1) represented by the following formula,
14. the method according to claim 13, wherein the hydrolysis reaction uses hydroxide base as the hydrolysis reagent, wherein the hydroxide base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, and a combination of two or more thereof.
15. The method of claim 14, wherein the hydroxide is potassium hydroxide.
16. The method according to claim 13, wherein the temperature of the hydrolysis reaction is controlled to 10 to 35 ℃.
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