CN106680384A - Ibuprofen and ketoprofen enantiomer resolution method - Google Patents
Ibuprofen and ketoprofen enantiomer resolution method Download PDFInfo
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Abstract
The invention discloses an ibuprofen and ketoprofen enantiomer resolution method. According to the method, ibuprofen menthyl acrylate or ketoprofen menthyl acrylate is dissolved with methanol, and then the dissolved matter is used as a test sample for high performance liquid chromatographic resolution, and finally an ibuprofen menthyl acrylate diastereomer or ketoprofen menthyl acrylate diastereomer is obtained, wherein the chromatographic column is YMC-ODS-C18; a mobile phase is mixed liquor of methanol and water or mixed liquor of acetonitrile and water; flow velocity is 0.6-0.8 mL/min; detection wavelength is 212-254 nm; and column temperature is 30-40 DEG C. The method for pre-column derivatization high-performance liquid chromatographic chiral resolution of ibuprofen and ketoprofen by the use of a chiral derivatization reagent is simple and feasible; the mobile phase is simple; there is no need to add a chiral additive; aftertreatment is simple; and the method is economic and practical, has high sensitivity, and can rapidly and effectively separate ibuprofen and ketoprofen.
Description
(1) technical field
The present invention relates to the method for splitting of a kind of ibuprofen and ketone ibuprofen enantiomer.
(2) background technology
2- substituted aryl propanoic acid analog derivatives are class I non-steroid anti-inflammatory and antalgic antibiotic medicine or synthesis non-steroidal anti-inflammatory
The key intermediate of analgesia anti-inflammation medicine.This kind of clinical drug has been widely used and into clinical trial including naproxen, cloth
Ibuprofen, ketoprofen, flurbiprofen etc. more than 20 are planted.Except S-NAP, other 2- aryl propionic non-steroids AIDs are all
With racemate form listing.Why this kind of medicine becomes the focus of intensive research, and one is due to their clinically extensive
Using, it is another, it is because while they have many common ground, its enantiomer has different biological characteristicses again.It is raw
The difference that thing scholarship and moral conduct is is included one in stereoselective protein binding, glucuronidation and metabolism, and this kind of medicine
Divide unidirectional conversion of the R- enantiomer to S- enantiomer.These different biological characteristicses also have impact on the pharmacodynamicss and medicine of medicine and move
Learn, therefore, the fractionation to 2- substituted 2-aryl propanoic derivatives enantiomer is particularly important.
At present, the acquisition research of 2- arylprops acids drug enantiomer is existing both at home and abroad much reports mainly have asymmetric
Synthetic method, bioanalysises and chromatography etc..Dissymmetric synthesis are the Perfected process for obtaining chiral drug, and the method is not using right
Catalyst is claimed to carry out induced reaction, then through a series of subsequent treatment, to obtain more pure enantiomer.2- arylpropionic acids
Using the available more pure single enantiomer of dissymmetric synthesis, the method is early stage single chiral 2- arylprop to class material
The main method that acid is obtained.The single enantiomer relative purity obtained using the method is higher, but prepared by the method
Journey is complicated, and sample subsequent treatment by-product is difficult to remove, and price is costly.
Biological resolution method, is typically with the biomaterials such as microbial cells, enzyme or animal vegetable tissue and raceme handss
Property medicine effect obtain single enantiomer method.The method is real mainly using the single stereo selectivity of the biomaterials such as enzyme
Matter is enzymatic kinetic resolution.The whole course of reaction time is longer, and reaction condition requirement is higher, and subsequent treatment is more multiple
It is miscellaneous.
Being usually used in the Chromatographic resolution method of 2- arylprop acids at present mainly has high performance capillary electrophoresis, high-speed counter-current color
Spectrometry and high performance liquid chromatography.High performance capillary electrophoresis separating rate is fast, but fractional dose is less.High-speed counter-current is adopted at this stage
The document that chromatography splits 2- arylprop acids is relatively fewer, and the method need to seek suitable dicyandiamide solution, and big multiselect
Select cyclodextrin series material to split 2- substituted aryl propanoic derivatives as chiral additiveses, cost is larger, more multiple
It is miscellaneous.
High performance liquid chromatography splits 2- substituted aryl propanoic derivatives, mainly there is stationary phase process and mobile phase additive process,
, using chiral material as fixing phase, expensive, relatively costly, the latter adds chiral reagent, such as ring in mobile phase for the former
Dextrin etc., post processing is complex, it is difficult to take more pure single enantiomer.
(3) content of the invention
It is an object of the present invention to provide the method for splitting of a kind of ibuprofen and ketone ibuprofen enantiomer, solves flowing
The post processing of phase additive process is complicated and Chiral Stationary Phases costly the problems such as.The present invention adopts 1R, 2S, 5R- (-)-Herba Menthae
Alcohol carries out esterification as chiral reagent to ibuprofen and ketone ibuprofen, obtains diastereomer, then uses achirality color
Spectrum post carries out fractionation separation, and the Chromatographic resolution method of this column front derivation 2- substituted aryl propanoic acid has relative to above method for splitting
Have efficiently, it is economical and practical, the advantages of separating degree is high.
The technical solution used in the present invention is：
The present invention provides the method for splitting of a kind of ibuprofen and ketone ibuprofen enantiomer, and methods described is：(1) it is pre-
Process：By ibuprofen or ketone ibuprofen and 1R, 2S, 5R- (-)-menthol and p-methyl benzenesulfonic acid mixing, in being dissolved in toluene, plus
Thermal agitation flows back, and TLC is tracked to after reaction terminates, and toluene is distilled off, and is carried out as leacheate with ethyl acetate with petroleum ether
Silica gel column chromatography, TLC detection effluent, collects target components, and rotary evaporation is dried, and obtains ibuprofen menthol ester or ketone group cloth
Ibuprofen menthol ester；The amount of the ibuprofen or ketone ibuprofen and 1R, 2S, 5R- (-)-menthol and p-methyl benzenesulfonic acid material
Ratio be 1:1.2:0.05, the volume of toluene consumption is calculated as 3ml/mmol with the amount of ibuprofen or ketone ibuprofen material；(2)
Split：Height is carried out after step (1) ibuprofen menthol ester or ketone ibuprofen menthol ester are dissolved with methanol as test sample
Effect liquid phase chromatogram method splits, and chromatographic column is YMC-ODS-C18 (4.6mm × 150mm, 10 μm), and mobile phase mixes for methanol with water
Liquid or acetonitrile and water mixed liquid, flow velocity is 0.6-0.8mL/min, and Detection wavelength is 212-254nm；Column temperature is 30-40 DEG C, is obtained
Ibuprofen menthol ester diastereomer or ketone ibuprofen menthol ester diastereomer.
Further, mobile phase when step (2) the ibuprofen menthol ester splits is acetonitrile and water with volume ratio 90:10
Mixed solution.
Further, mobile phase when step (2) the ketone ibuprofen menthol ester splits is methanol and water with volume ratio
75:25 mixed solution.
Further, flow velocity when step (2) the ibuprofen menthol ester splits is 0.6mL/min, and mobile phase is acetonitrile
With water volume ratio 90:10, Detection wavelength is 254nm, and column temperature is 30 DEG C.
Further, flow velocity when step (2) the ketone ibuprofen menthol ester splits is 0.8mL/min, and mobile phase is
Methanol and water volume ratio 80:20, Detection wavelength is 254nm, and column temperature is 30 DEG C.
According to the present invention, because esterification is reversible reaction, therefore need to be carried out at dehydration using water knockout drum in this course of reaction
Reason, reaction process is tracked detection using TLC, and after reaction terminates, is isolated and purified using 200-300 mesh silicagel columns.
Compared with prior art, the utilization chiral derivatizing agent that the present invention is adopted carries out post to ibuprofen and ketone ibuprofen
Method is simple for front derivatization Chiral Resolution in High Performance Liquid Chromatography, and mobile phase is simple, it is not necessary to adds chiral additiveses, locates afterwards
Reason is simple, and economical and practical, and sensitivity is high, can fast and effectively separate 2- substituted aryl propanoic derivatives (ibuprofen and ketone group
Ibuprofen).
(4) illustrate
Fig. 1 is the ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 1；
Fig. 2 is the ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 3；
Fig. 3 is the ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 4；
Fig. 4 is the ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 5；
Fig. 5 is the ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 6；
Fig. 6 is the ketone ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 7；
Fig. 7 is the ketone ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 8；
Fig. 8 is the ketone ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 9；
Fig. 9 is the ketone ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 10；
Figure 10 is the ketone ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 11；
Figure 11 is the ketone ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 12；
Figure 12 is the ketone ibuprofen menthyl ester liquid chromatograph separation graph of embodiment 13.
(5) specific embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This：
Embodiment 1：Ibuprofen splits
(1) 1R, 2S, 5R- (-)-menthol (1.87g, 12mmol), ibuprofen are sequentially added in round-bottomed flask
(2.06g, 10mmol) and p-methyl benzenesulfonic acid (0.1g, 0.5mmol), its mol ratio is 1.2:1：0.05, in being dissolved in 30mL toluene,
Heated and stirred flows back, TLC detection reaction process.After question response terminates, toluene is distilled off, with petroleum ether and ethyl acetate conduct
Leacheate carries out 200-300 mesh silica gel column chromatographies, and TLC detection effluent, rotary evaporation is dried, and obtains ibuprofen menthol ester pure
Product 1.99g.
(2) the ibuprofen menthol ester obtained by 10mg steps (1) is taken, is transferred in 25ml volumetric flasks after being dissolved with methanol,
And methanol constant volume is used, obtain need testing solution；Need testing solution is carried out into high performance liquid chromatography point by following liquid phase chromatogram conditions
Analysis；
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Acetonitrile-water=90:10, v/v is mobile phase；Flow velocity
For 0.6mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in figure 1, can from figure
To find out, the appearance time of two diastereomers is respectively 30.106min and 31.908min, and separating degree is 1.613.
Embodiment 2：Ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1.
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Mobile phase is respectively acetonitrile
100:0,95:5,90:10,85:15,80:20；Flow velocity is 0.6mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；Sample introduction
The μ L of volume 10.
Need testing solution is respectively adopted above-mentioned liquid phase chromatogram condition and separates, and two isomer separation degree of gained are as shown in table 1：
Isomer separation degree under the different condition of table 1
| Acetonitrile-water | 100:0 | 95:5 | 90:10 | 85:15 | 80:20 |
| Separating degree | 1.163 | 1.249 | 1.239 | 1.205 | 1.100 |
As can be seen from Table 1, with the change of acetonitrile and water ratio, the separating degree of two isomers is slightly changed, but shadow
Sound is less, and this method suitability is higher.
Embodiment 3：Ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1.
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Acetonitrile-water=90:10, v/v is mobile phase；Flow velocity
For 0.7mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in Fig. 2 can from figure
To find out, the appearance time of two diastereomers is respectively 26.387min and 27.982min, and separating degree is 1.240.
Embodiment 4：Ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Acetonitrile-water=90:10, v/v is mobile phase；Flow velocity
For 0.8mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in figure 3, can from figure
To find out, the appearance time of two diastereomers is respectively 23.207min and 24.610min, and separating degree is 1.215.
Embodiment 5：Ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Acetonitrile-water=90:10, v/v is mobile phase；Flow velocity
For 0.6mL/min；Detection wavelength is 254nm；Column temperature is 25 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in figure 4, can from figure
To find out, the appearance time of two diastereomers is respectively 28.253min and 29.879min, and separating degree is 1.185.
Embodiment 6：Ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Acetonitrile-water=90:10, v/v is mobile phase；Flow velocity
For 0.6mL/min；Detection wavelength is 254nm；Column temperature is 35 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in figure 5, can from figure
To find out, the appearance time of two diastereomers is respectively 26.232min and 27.663min, and separating degree is 1.123.
Embodiment 7：Ketone ibuprofen splits
(1) 1R, 2S, 5R- (-)-menthol (1.87g, 12mmol), ketone ibuprofen are sequentially added in round-bottomed flask
(2.54g, 10mmol) and p-methyl benzenesulfonic acid (0.1g, 0.5mmol), its mol ratio is 1.2:1：0.05, in being dissolved in 30mL toluene,
Heated and stirred flows back, TLC detection reaction process.After question response terminates, toluene is distilled off, with petroleum ether and ethyl acetate conduct
Leacheate carries out column chromatography, and TLC detection effluent, rotary evaporation is dried, and obtains ketone ibuprofen menthol ester sterling 2.45g.
(2) the ketone ibuprofen menthol ester obtained by 10mg steps (1) is taken, after being dissolved with methanol 25ml volumetric flasks is transferred to
In, and methanol constant volume is used, obtain need testing solution；Need testing solution is carried out into high performance liquid chromatography by following liquid phase chromatogram conditions
Analysis；
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Methanol-water=75:25, v/v is mobile phase；Flow velocity
For 0.8mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in fig. 6, can from figure
To find out, the appearance time of two diastereomers is respectively 68.916min and 73.790min, and separating degree is 1.013.
Embodiment 8：Ketone ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Methanol-water=80:20, v/v is mobile phase；Flow velocity
For 0.8mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in fig. 7, can from figure
To find out, the appearance time of two diastereomers is respectively 30.210min and 31.969min, and separating degree is 0.749.
Embodiment 9：Ketone ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Methanol-water=70:30, v/v is mobile phase；Flow velocity
For 0.8mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in figure 8, can from figure
To find out, the appearance time of two diastereomers is respectively 175.223min and 189.350min, and separating degree is 1.451.
Embodiment 10：Ketone ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Methanol-water=75:25, v/v is mobile phase；Flow velocity
For 0.7mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；The μ L of sampling volume 10.
Need testing solution is using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition as shown in figure 9, can from figure
To find out, the appearance time of two diastereomers is respectively 82.902min, and ((peak b), separating degree is for peak a) and 88.936min
1.184。
Embodiment 11：Ketone ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Methanol-water=75:25, v/v is mobile phase；Flow velocity
For 0.9mL/min；Detection wavelength is 254nm；Column temperature is 30 DEG C；The μ L of sampling volume 10.
Need testing solution is as shown in Figure 10 using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition, can from figure
To find out, the appearance time of two diastereomers is respectively 61.889min, and ((peak b), separating degree is for peak a) and 66.281min
0.998。
Embodiment 12：Ketone ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Methanol-water=75:25, v/v is mobile phase；Flow velocity
For 0.8mL/min；Detection wavelength is 254nm；Column temperature is 25 DEG C；The μ L of sampling volume 10.
Need testing solution is as shown in figure 11 using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition, can from figure
To find out, the appearance time of two diastereomers is respectively 77.322min, and ((peak b), separating degree is for peak a) and 83.034min
1.190。
Embodiment 13：Ketone ibuprofen splits
(1) with step (1) in embodiment 1.
(2) with step (2) in embodiment 1
It is analyzed using following liquid phase analysis condition：
Chromatographic column：YMC-ODS-C18,4.6mm × 150mm, 10 μm；Methanol-water=75:25, v/v is mobile phase；Flow velocity
For 0.8mL/min；Detection wavelength is 254nm；Column temperature is 35 DEG C；The μ L of sampling volume 10.
Need testing solution is as shown in figure 12 using the liquid chromatograph separation graph obtained by above-mentioned liquid phase chromatogram condition, can from figure
To find out, the appearance time of two diastereomers is respectively 67.130min, and ((peak b), separating degree is for peak a) and 71.684min
1.019。
Claims (5)
1. the method for splitting of a kind of ibuprofen and ketone ibuprofen enantiomer, it is characterised in that methods described is：(1) pre- place
Reason：By ibuprofen or ketone ibuprofen and 1R, 2S, 5R- (-)-menthol and p-methyl benzenesulfonic acid mixing, in being dissolved in toluene, heating
It is stirred at reflux, TLC is tracked to after reaction terminates, and toluene is distilled off, and silicon is carried out as leacheate with petroleum ether and ethyl acetate
Plastic column chromatography, TLC detection effluent, collects target components, and rotary evaporation is dried, and obtains ibuprofen menthol ester or ketone group cloth Lip river
Fragrant menthol ester；The amount of the ibuprofen or ketone ibuprofen and 1R, 2S, 5R- (-)-menthol and p-methyl benzenesulfonic acid material it
Than for 1:1.2:0.05, the volume of toluene consumption is calculated as 3ml/mmol with the amount of ibuprofen or ketone ibuprofen material；(2) tear open
Point：Carry out efficiently as test sample after step (1) ibuprofen menthol ester or ketone ibuprofen menthol ester are dissolved with methanol
Liquid chromatography splits, and chromatographic column is YMC-ODS-C18, and mobile phase is methanol and water mixed liquid or acetonitrile and water mixed liquid, is flowed
Speed is 0.6-0.8mL/min, and Detection wavelength is 212-254nm；Column temperature is 30-40 DEG C, obtains ibuprofen menthol ester diastereomeric
Isomer or ketone ibuprofen menthol ester diastereomer.
2. the method for splitting of ibuprofen as claimed in claim 1 and ketone ibuprofen enantiomer, it is characterised in that step (2)
Mobile phase when the ibuprofen menthol ester splits is acetonitrile and water with volume ratio 100-80:The mixed liquor of 0-20.
3. the method for splitting of ibuprofen as claimed in claim 1 and ketone ibuprofen enantiomer, it is characterised in that step (2)
Mobile phase when the ketone ibuprofen menthol ester splits is methanol and water with volume ratio 70-80:The mixed liquor of 20-30.
4. the method for splitting of ibuprofen as claimed in claim 1 and ketone ibuprofen enantiomer, it is characterised in that step (2)
Flow velocity when the ibuprofen menthol ester splits is 0.6mL/min, and mobile phase is acetonitrile and water volume ratio 90:10, detect ripple
A length of 254nm, column temperature is 30 DEG C.
5. the method for splitting of ibuprofen as claimed in claim 1 and ketone ibuprofen enantiomer, it is characterised in that step (2)
Flow velocity when the ketone ibuprofen menthol ester splits is 0.8mL/min, and mobile phase is methanol and water volume ratio 75:25, inspection
Survey wavelength is 254nm, and column temperature is 30 DEG C.
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| CN116165306A (en) * | 2023-04-25 | 2023-05-26 | 湖南九典制药股份有限公司 | Analysis and determination method and application of related substances in ketoprofen gel plaster |
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| CN107132297B (en) * | 2017-06-30 | 2019-08-13 | 方达医药技术(上海)有限公司 | A kind of analyzing detecting method of pramiconazole optical isomer |
| CN110204436A (en) * | 2019-06-04 | 2019-09-06 | 斯诺科(杭州)生物科技有限公司 | A kind of method for splitting of naproxen enantiomter |
| CN112526013A (en) * | 2020-11-20 | 2021-03-19 | 人福普克药业（武汉）有限公司 | Method for detecting concentration of related substances in ibuprofen medicament based on ultra-high liquid chromatography |
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