CN106749322B - Process for separating enantiomers of ofloxacin - Google Patents
Process for separating enantiomers of ofloxacin Download PDFInfo
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- CN106749322B CN106749322B CN201510819239.6A CN201510819239A CN106749322B CN 106749322 B CN106749322 B CN 106749322B CN 201510819239 A CN201510819239 A CN 201510819239A CN 106749322 B CN106749322 B CN 106749322B
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
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Abstract
The invention discloses a method for separating ofloxacin enantiomer. The method comprises the following steps: (1) dissolving an ofloxacin sample so as to obtain an ofloxacin solution; (2) separating the ofloxacin enantiomer in the ofloxacin solution by using a simulated moving bed chromatography system, wherein the chromatographic conditions are as follows: a chromatographic column: chiralcel OD-H chiral column; stationary phase: the surface is coated with cellulose-tri [3, 5-xylyl carbamate ] silica gel; mobile phase: contains the mixed liquid of ethanol, n-hexane and phosphoric acid. The invention has simple process and stable and reliable product, and can be used for industrial mass production.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to chiral drug resolution, and more particularly relates to a method for separating an ofloxacin enantiomer.
Background
Ofloxacin (compound shown in formula 1) is a quinolone broad-spectrum antibacterial drug, and mainly inhibits the synthesis of bacterial DNA by selectively inhibiting the activity of bacterial DNA gyrase, thereby achieving the bactericidal effect. The drug ofloxacin is a racemic compound of levorotatory isomer and dextrorotatory isomer thereof, wherein the levorotatory antibacterial activity is stronger. Levofloxacin was first marketed in japan in 1993 and is used for the treatment of respiratory tract infections, urogenital infections, and skin soft tissue infections.
At present, a technical method for preparing ofloxacin by simulated moving bed chromatographic resolution is not seen.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, one object of the present invention is to provide a method for separating the enantiomer of ofloxacin, which can separate the levorotatory isomer and the dextrorotatory isomer of ofloxacin, and the purity can reach more than 90%. The invention has simple process, more accurate components and contents of the product medicine, more stable and reliable medicine effect and can be used for industrialized mass production.
In one aspect of the invention, the invention provides a process for separating enantiomers of ofloxacin. According to an embodiment of the invention, the method comprises: (1) dissolving an ofloxacin sample so as to obtain an ofloxacin solution; (2) separating the ofloxacin enantiomer in the ofloxacin solution by using a simulated moving bed chromatography system, wherein the chromatographic conditions are as follows: a chromatographic column: chiralcel OD-H chiral column; stationary phase: the surface is coated with cellulose-tri [3, 5-xylyl carbamate ] silica gel; mobile phase: contains the mixed liquid of ethanol, n-hexane and phosphoric acid.
According to the method for separating the enantiomer of the ofloxacin, provided by the embodiment of the invention, the levofloxacin and the dextrofloxacin can be efficiently separated, and the purity of the levofloxacin and the dextrofloxacin is high. Moreover, the method has simple and convenient process, can realize continuous production and has stable and good product quality. In addition, the mixture of ethanol, normal hexane and phosphoric acid is used as a mobile phase, so that the method is non-toxic and harmless, the mobile phase can be fully recycled, the method is green and environment-friendly, and the cost is saved.
In addition, the method for preparing ofloxacin by simulated moving bed chromatography separation according to the embodiment of the invention can also have the following additional technical characteristics:
in some embodiments of the present invention, in the mixed solution containing ethanol, n-hexane and phosphoric acid, the volume ratio of the ethanol, the n-hexane and the phosphoric acid is (0-100): (0-100): (0-100), preferably (80-100): (0-20): (0.5-1), more preferably 95; 5: 0.5. thereby facilitating separation.
In some embodiments of the invention, the simulated moving bed chromatography system comprises: a chromatographic column area: the chromatographic column area comprises 4 ~ 12 chromatographic columns, and the chromatographic column area is divided into I, II, III, IV district, wherein, every district all includes: 1-3 chromatographic columns; a sample injection pump; an elution pump; an extraction pump; and a solenoid valve. The more the number of chromatographic columns is, the better the separation effect is, but the longer the separation time is, and a great deal of research by the inventor finds that the chromatographic column area consists of 4-12 chromatographic columns, so that the optimal combination of the separation effect and the separation time is achieved.
Referring to FIG. 1, in some embodiments of the present invention, the SMB system consists of 4-12 chromatographic columns, divided into I, II, III, and IV zones, each zone having 1-3 chromatographic columns. Wherein, the I area is positioned between the eluent inlet and the extract outlet, and the desorption of the dextro-ofloxacin is mainly realized in the I area; the II area is positioned between the extract outlet and the sample inlet, and the dextro-ofloxacin is repeatedly adsorbed, resolved and concentrated in the II area; the III zone is positioned between the sample inlet and the raffinate outlet, and levofloxacin is obtained in the III zone; the IV area is positioned between the eluent inlets of the raffinate outlets, on one hand, the eluent in the III area can be recycled when entering the IV area, and on the other hand, the IV area separates the III area from the I area, so that the levofloxacin in the raffinate is prevented from entering the I area.
In some embodiments of the invention, the method comprises: (1) dissolving the ofloxacin sample in a mobile phase so as to obtain the ofloxacin solution, wherein the concentration of ofloxacin in the ofloxacin solution is 0.1-200 mg/ml; (2) and according to the adjustment of the switching time of the electromagnetic valve, separating to obtain levofloxacin and dextrofloxacin products.
In some embodiments of the invention, levofloxacin and dextrofloxacin products are separated according to the switching time adjustment of the electromagnetic valve in the simulated moving bed chromatography system.
In some embodiments of the present invention, the particle size of the packing in the chromatography column is 10 to 60 μm, preferably 20 to 30 μm. Therefore, the separation degree of each chiral component in the ofloxacin can be further improved. The smaller the particle size, the better the separation. However, if the particle size is too small, the column pressure increases. When the particle size of the filler is 10-60 μm, especially 20-30 μm, the separation effect is good, and the column pressure is appropriate.
In some embodiments of the present invention, step (3) may further concentrate, recrystallize, filter, and dry the levofloxacin and dextrofloxacin solutions, respectively, to obtain levofloxacin and dextrofloxacin with purity of more than 95%.
In some embodiments of the invention, the flow rate of an elution pump in the simulated moving bed chromatography system is 0ml/min to 100ml/min, and the pressure is 0MPa to 10 MPa; the flow rate of the sample injection pump is 0 ml/min-50 ml/min, and the pressure is 0-10 MPa; the flow rate of the extraction pump is 0 ml/min-100 ml/min, and the pressure is 0-10 MPa. Therefore, the separation degree of each chiral component in the ofloxacin can be further improved.
In some embodiments of the present invention, the switching time of the solenoid valve is 5min to 20 min. Therefore, the high-purity levofloxacin and dextrofloxacin can be conveniently obtained.
In some embodiments of the invention, the operating temperature of the simulated moving bed chromatography system is 20-40 ℃, preferably 25-30 ℃. Therefore, the separation degree of each chiral component in the ofloxacin can be further improved.
In some embodiments of the invention, the simulated moving bed chromatography system is controlled by a PLC program to realize continuous feeding and continuous discharging.
The method for separating the ofloxacin enantiomer has at least one of the following beneficial effects:
(1) the levorotatory body and the dextrorotatory body of the ofloxacin are separated by a simulated moving bed chromatography technology, and the purity of the levorotatory body and the dextrorotatory body of the ofloxacin can reach more than 90 percent.
(2) The process flow is very simple and convenient, the continuous production can be realized, the content of levorotatory body and dextrorotatory body of the ofloxacin in the product is accurate, and the quality of the medicine is more stable.
(3) The whole process does not relate to toxic and harmful substances, adopts a mixture of ethanol, normal hexane and phosphoric acid as a mobile phase, can be fully recycled, is green and environment-friendly, and saves cost.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 shows a schematic diagram of a simulated moving bed chromatography system according to an embodiment of the invention.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The ofloxacin raw material used in the embodiment of the invention is self-made by the applicant.
The general method comprises the following steps:
1. equipment and condition selection
A simulated moving bed chromatographic system is adopted, and the system consists of an elution pump, a sample injection pump, an extraction pump, a chromatographic column, an electromagnetic valve, a one-way valve, a temperature controller, a PLC system controller and a computer. And the sample solution and the eluent are respectively injected into the system from a sample solution inlet and an eluent inlet, two enantiomer monomers of the ofloxacin respectively flow out from two outlets of the raffinate and the extract, and the sample solution and eluent inlet, the extract and raffinate outlets are switched to the next chromatographic column along the flowing direction of the mobile phase at regular intervals.
2. Chromatographic column packing and mobile phase (solvent) selection
The method is characterized in that cellulose-tri [3, 5-xylyl carbamate ] silica gel is used as a chiral stationary phase, the filler granularity is 10-60 mu m, and a mobile phase is a mixture of ethanol, n-hexane and phosphoric acid.
3. Separation step
(1) After a sample is dissolved by a mobile phase, the sample enters a system through a sample injection pump, the system is divided into 4 areas, the more chromatographic columns are, the higher the separation purity is, but the higher the complexity of the system and the system pressure is, most suitably 4-16 chromatographic columns, and the controller of the simulated moving bed chromatographic system is used for periodically controlling the opening and closing of the electromagnetic valve to ensure that an elution port, a sample injection port, an extraction liquid outlet and a raffinate liquid outlet are switched at regular time along the direction of the mobile phase, so that two enantiomer monomers of ofloxacin flow out of the system from the extraction liquid outlet and the raffinate liquid outlet;
(2) concentrating and recrystallizing the obtained product solution to obtain a qualified product with the purity of more than 90%;
(3) analysis of the finished product
Mobile phase: ethanol: n-hexane: phosphoric acid 95: 5: 0.5
Flow rate: 0.5mL/min
A pump: 10ml analysis pump
A chromatographic column: chiralcel OD-H (4.6X 250mm, 20 μm)
A detector: ultraviolet detector
Column temperature: 25 deg.C
Detection wavelength: 294 nm.
Example 1
Mobile phase: ethanol: n-hexane: phosphoric acid 95: 5: 0.5
Flow rate: 1ml/min
Sample introduction concentration: ofloxacin racemate: 0.2mg/ml
Flow rate of sample injection liquid: v1 ═ 0.1ml/min
Flow rate of mobile phase: v2 ═ 1.0ml/min
Flow rate of flushing liquid: v3 ═ 2.0ml/min
F, pump pressure: 6.8MPa
P pump pressure: 7.5MPa
Pump pressure: 6.8MPa
Switching time: 8.5min
Column temperature: 25 deg.C
Analysis of the finished product
And analyzing the composition of the extraction liquid and the raffinate by using a chiral column Chiralcel OD-H, wherein the content of the levofloxacin or the dextrofloxacin is 100 percent and 98 percent respectively.
Example 2
Mobile phase: ethanol: n-hexane: phosphoric acid 85: 15: 1
Flow rate: 1ml/min
Sample introduction concentration: ofloxacin racemate: 0.2mg/ml
Flow rate of sample injection liquid: v1 ═ 0.1ml/min
Flow rate of mobile phase: v2 ═ 1.0ml/min
Flow rate of flushing liquid: v3 ═ 0.5ml/min
F, pump pressure: 6.5MPa
P pump pressure: 4.5MPa
Pump pressure: 6.5MPa
Switching time: 8.5min
Column temperature: 25 deg.C
Analysis of the finished product
And analyzing the composition of the extraction liquid and the raffinate by using a chiral column Chiralcel OD-H, wherein the content of the levofloxacin or the dextrofloxacin is respectively 90% and 100%.
Example 3
Mobile phase: ethanol: n-hexane: phosphoric acid 90: 10: 0.5
Flow rate: 1ml/min
Sample introduction concentration: ofloxacin racemate: 0.2mg/ml
Flow rate of sample injection liquid: v1 ═ 0.1ml/min
Flow rate of mobile phase: v2 ═ 1.0ml/min
Flow rate of flushing liquid: v3 ═ 2.0ml/min
F, pump pressure: 6.8MPa
P pump pressure: 7.5MPa
Pump pressure: 7.0MPa
Switching time: 8.5min
Column temperature: 25 deg.C
Analysis of the finished product
And analyzing the composition of the extraction liquid and the raffinate by using a chiral column Chiralcel OD-H, wherein the content of the levofloxacin or the dextrofloxacin is 100 percent and 90 percent respectively.
Comparative example 1
Mobile phase: ethanol: n-hexane: phosphoric acid 75: 5: 0.5
Flow rate: 1ml/min
Sample introduction concentration: ofloxacin racemate: 0.2mg/ml
Flow rate of sample injection liquid: v1 ═ 0.1ml/min
Flow rate of mobile phase: v2 ═ 1.0ml/min
Flow rate of flushing liquid: v3 ═ 2.0ml/min
F, pump pressure: 6.1MPa
P pump pressure: 8.2MPa
Pump pressure: 6.6MPa
Switching time: 9min
Column temperature: 25 deg.C
Analysis of the finished product
And analyzing the composition of the extraction liquid and the raffinate by using a chiral column Chiralcel OD-H, wherein the content of the levofloxacin or the dextrofloxacin is respectively 75% and 85%, the purity of the levofloxacin or the dextrofloxacin is low, and the separation effect is obviously lower than that of the examples 1-3.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (7)
1. A process for separating enantiomers of ofloxacin comprising:
(1) dissolving the ofloxacin sample in a mobile phase so as to obtain the ofloxacin solution, wherein the concentration of ofloxacin in the ofloxacin solution is 0.1-200 mg/ml;
(2) and separating the ofloxacin enantiomer in the ofloxacin solution by using a simulated moving bed chromatographic system, wherein the levofloxacin and the dextrofloxacin are separated according to the adjustment of the switching time of the electromagnetic valve, and the chromatographic conditions are as follows:
a chromatographic column: chiralcel OD-H chiral column;
stationary phase: the surface is coated with cellulose-tri [3, 5-xylyl carbamate ] silica gel;
mobile phase: the mixed liquid contains ethanol, n-hexane and phosphoric acid, wherein in the mixed liquid containing the ethanol, the n-hexane and the phosphoric acid, the volume ratio of the ethanol to the n-hexane to the phosphoric acid is (80-100): (0-20): (0.5-1);
the simulated moving bed chromatography system comprises:
a chromatographic column area: the chromatographic column area comprises 4 ~ 12 chromatographic columns, and the chromatographic column area is divided into I, II, III, IV district, wherein, every district all includes:
1-3 chromatographic columns;
the flow rate of the sample injection pump is 0 ml/min-50 ml/min, and the pressure is 0-10 MPa;
the flow rate of the elution pump is 0 ml/min-100 ml/min, and the pressure is 0-10 MPa;
the flow rate of the extraction pump is 0 ml/min-100 ml/min, and the pressure is 0-10 MPa; and
the electromagnetic valve is switched for 5-20 min;
the operating temperature of the simulated moving bed chromatographic system is 20-40 ℃.
2. The method according to claim 1, wherein in the mixed solution containing ethanol, n-hexane and phosphoric acid, the volume ratio of ethanol, n-hexane and phosphoric acid is 95: 5: 0.5.
3. the method according to claim 1, wherein the packing in the chromatographic column has a particle size of 10 to 60 μm.
4. The method according to claim 3, wherein the particle size of the packing in the chromatographic column is 20 to 30 μm.
5. The method of claim 1, further comprising:
concentrating, recrystallizing, filtering and drying the levofloxacin and the dextrofloxacin to obtain a pure levofloxacin product and a pure dextrofloxacin product, wherein the purities of the levofloxacin product and the pure dextrofloxacin product are not lower than 90%.
6. The method according to claim 1, wherein the operating temperature of the simulated moving bed chromatography system is 25-30 ℃.
7. The method of claim 1, wherein the simulated moving bed chromatography system is controlled by a PLC program to achieve continuous feed and continuous take off.
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| CN103788145A (en) * | 2012-10-31 | 2014-05-14 | 江苏汉邦科技有限公司 | Method for splitting tribenoside by simulated moving bed |
| CN103788064A (en) * | 2012-10-31 | 2014-05-14 | 江苏汉邦科技有限公司 | Simulated moving bed chromatographic separation method for omeprazole enantiomer |
| CN103787873A (en) * | 2012-11-01 | 2014-05-14 | 江苏汉邦科技有限公司 | Method for splitting ketoprofen enantiomer by simulated moving bed chromatography |
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Address after: 430075 Guanggu Biological City B3-4, 666 High-tech Avenue, Donghu New Technology Development Zone, Wuhan City, Hubei Province Patentee after: Sino US huashitong biomedical technology (Wuhan) Co.,Ltd. Address before: 430075 Guanggu Biological City B3-4, 666 High-tech Avenue, Donghu New Technology Development Zone, Wuhan City, Hubei Province Patentee before: WATERSTONE PHARMACEUTICALS(WUHAN) Co.,Ltd. |