CN103570564B - A kind of Propafenone drug enantiomer method for splitting - Google Patents
A kind of Propafenone drug enantiomer method for splitting Download PDFInfo
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Abstract
The invention provides a kind of Propafenone drug enantiomer method for splitting.The method with Propafenone hydrochloride for split object, first Propafenone hydrochloride is converted into Propafenone episome, with L-TARTARIC ACID ester class and boric acid as resolution reagent, L-TARTARIC ACID ester class is added in organic phase, boric acid adds in aqueous phase, adopts high-speed countercurrent chromatography to obtain left-handed Propafenone and dextrorotation Propafenone.Compared with prior art, beneficial effect of the present invention is mainly reflected in: adopt present method resolving chiral medicine Propafenone can reach higher resolution, and the method is applicable to the preparative counter current chromatograph of various model, can be separated the monomer obtaining left-handed Propafenone and dextrorotation Propafenone.
Description
(1) technical field
The present invention relates to a kind of Propafenone drug enantiomer method for splitting.
(2) background technology
All may there is significant difference in chiral drug metabolic process in vivo, pharmacologically active and toxicity, therefore find efficiently, easily method for splitting seem particularly important.Propafenone is that the film of broad-spectrum high efficacy suppresses class anti-arrhythmic, the clinical property ectopic beat be mainly used on prevention and therapy room property or room, and property tachycardia on room property or room, quiver outbreak and preexcitation syndrome etc. in room after electrical conversion, wherein dextrorotation Propafenone has stronger beta-receptor blocking effect, and left-handed Propafenone does not have, and the existence of left-handed Propafenone enhances the beta-receptor blocking effect of dextrorotation Propafenone.At present, the method splitting propafenone enantiomers mainly contains high performance liquid chromatography, capillary electrophoresis, paired ion chromatography, tlc etc.
From the nineties in 20th century, increasing country starts policy and the governing principle of making chiral drug exploitation.1992, U.S. food and drug administration (FDA) issue about in the governing principle of chiral drug, just explicitly call for all information that must comprise the chemistry of chiral drug, pharmacology, toxicology and clinical effect at the application paper of the relevant new drug submitted to FDA.Therefore, carry out the fractionation of chiral drug and obtain single chiral drug, having become an important branch in separation science field.
High-speed countercurrent chromatography (high-speed countercurrent chromatography, HSCCC) be a kind of liquid liquid distribution technique without solid state support body or carrier grown up the eighties in 20th century, there is the irreplaceable advantage of other chromatographic separation technologies many, as do not adopted any solid phase carrier because of adverse current chromatogram, can get rid of because the irreversible adsorption of solid phase carrier to sample causes the loss of sample in analytical separation process completely, the impacts such as inactivation and pollution sex change, thus it is high to realize the rate of recovery, high purity, the better result that circulation ratio is high, also the separation and purification of large preparation amount material can be used for.In recent years, all constantly have new HSCCC technology and application achievements to report out every year in the world, domestic also have increasing experts and scholars to add its studying team.
(3) summary of the invention
The object of this invention is to provide a kind of method adopting high-speed countercurrent chromatography to split Propafenone drug enantiomer.
The technical solution used in the present invention is:
A kind of Propafenone drug enantiomer method for splitting, described method comprises:
(1) organic solvent containing L-TARTARIC ACID ester and the acetic acid/triethylamine buffer solution containing boric acid are mixed according to volume ratio 1:1, stratification, be separated and obtain organic phase and aqueous phase, for subsequent use; In described organic solvent, the concentration of L-TARTARIC ACID ester is 0.02 ~ 0.5mol/L;
The pH of described acetic acid/triethylamine buffer solution containing boric acid is 2.0 ~ 5.0, and the concentration of its mesoboric acid is 0.01 ~ 0.30mol/L;
Described organic solvent is the substituted arene of the halogenated alkane of C1 ~ C8, the alkane of C1 ~ C8, the ether of C2 ~ C8 or C6 ~ C12, and the substituting group of described substituted arene is one or more, and described substituting group is independently selected from the alkyl of halogen or C1 ~ C4 separately;
Described L-TARTARIC ACID ester is one of following: the just own ester of L-TARTARIC ACID, the positive butyl ester of L-TARTARIC ACID, L-TARTARIC ACID n-octyl, L-TARTARIC ACID n-pentyl ester, L-TARTARIC ACID isobutyl ester or L-TARTARIC ACID-2-ethylhexyl;
(2) Propafenone hydrochloride is converted into Propafenone episome, and by step (1) gained aqueous phase dissolved, makes the sample of 0.1 ~ 15mg/ml, for subsequent use as sample introduction liquid;
(3) high-speed countercurrent chromatography is adopted to split Propafenone: the organic phase obtained with step (1) respectively and aqueous phase are stationary phase and moving phase, countercurrent chromatography separation column is filled up stationary phase, column temperature is 5 ~ 30 DEG C, opening speed controller, rotating speed is 500 ~ 2000rpm, with the flow velocity of 0.2 ~ 3.0ml/min, moving phase is pumped in post, reach after fluid dynamic equilibrium until two phase solvent system and (just think when moving phase flows out from column outlet and reach balance), step (2) sample introduction liquid is by sampling valve sample introduction, detect with the UV-detector of wavelength 190 ~ 400nm, according to ultraviolet detection spectrogram, collect leading peak elutriant and postpeak elutriant respectively,
(4) from step (3), collect recovery in the leading peak elutriant obtained and postpeak elutriant respectively obtain the monomer of left-handed Propafenone and dextrorotation Propafenone.
The present invention with Propafenone hydrochloride for split object, first Propafenone hydrochloride is converted into Propafenone episome, with L-TARTARIC ACID ester class and boric acid as resolution reagent, L-TARTARIC ACID ester class is added in organic phase, boric acid adds in aqueous phase, adopts high-speed countercurrent chromatography to obtain left-handed Propafenone and dextrorotation Propafenone.
Preferably, described organic solvent is one of following or wherein two or more mixture: chloroform, methylene dichloride, toluene, chlorobenzene, normal hexane, normal heptane, Skellysolve A, hexanaphthene, sherwood oil, ether, methyl tertiary butyl ether, be more preferably chloroform or methylene dichloride, most preferably be chloroform.
Described L-TARTARIC ACID ester is preferably the just own ester of L-TARTARIC ACID or the positive butyl ester of L-TARTARIC ACID, is more preferably the positive butyl ester of L-TARTARIC ACID.
PH=2 ~ 4 of the acetic acid/triethylamine buffer solution containing boric acid that the present invention is preferably described, wherein boric acid concentration is preferably 0.1 ~ 0.2mol/L; The pH=3.4 of the most preferably described acetic acid/triethylamine buffer solution containing boric acid, wherein boric acid concentration is 0.1mol/L.
In the organic solvent that the present invention is preferably described, the concentration of L-TARTARIC ACID ester is 0.1 ~ 0.2mol/L, most preferably is 0.1mol/L.
In step of the present invention (2), by following method, Propafenone hydrochloride is converted into Propafenone episome: get Propafenone hydrochloride and join in 1 ~ 2mol/L sodium hydroxide solution, be heated to 40 ~ 50 DEG C and stir 2 ~ 3min, then dichloromethane extraction is used, gained organic phase milli-Q water to neutral, namely obtain crude product with anhydrous sodium sulfate drying, filtration, filtrate steaming removal solvent, crude product methylene dichloride dissolves and adds several normal hexane recrystallizations, obtains Propafenone episome.
In step of the present invention (3), after high-speed countercurrent chromatography splits, carry out high performance liquid phase detection by collecting the elutriant obtained, the purity of two monomer elutriants all can be greater than 90%.In split process, the column temperature of preferred countercurrent chromatography separation column is 5 ~ 15 DEG C; Preferably with the flow velocity of 0.5 ~ 2.0ml/min, moving phase is pumped in post.
In step of the present invention (4), from leading peak elutriant and postpeak elutriant, reclaim the monomer of left-handed Propafenone and dextrorotation Propafenone respectively by following method: by leading peak elutriant or postpeak elutriant alkalization to pH be 9 ~ 14, direct dichloromethane extraction after separating out a large amount of white powder, namely the water washing of dichloromethane layer saturated common salt obtains crude product to neutrality, anhydrous sodium sulfate drying, filtration, filtrate steaming removal solvent, and crude product methylene dichloride dissolves and adds left-handed Propafenone monomer or the dextrorotation Propafenone monomer that several normal hexane recrystallizations can obtain purifying.Wherein leading peak elutriant or the alkalization of postpeak elutriant available hydrogen sodium hydroxide solution, concentration of sodium hydroxide solution can be 1 ~ 2mol/L.
Preferably, described method is as follows:
(1) chloroform containing the positive butyl ester of L-TARTARIC ACID and the acetic acid/triethylamine buffer solution containing boric acid are mixed according to volume ratio 1:1, stratification, be separated and obtain organic phase and aqueous phase, for subsequent use; In described chloroform, the concentration of L-TARTARIC ACID ester is 0.1 ~ 0.2mol/L; The pH of described acetic acid/triethylamine buffer solution containing boric acid is 2.0 ~ 4.0, and the concentration of its mesoboric acid is 0.1 ~ 0.2mol/L;
(2) getting Propafenone hydrochloride joins in the sodium hydroxide solution of 1 ~ 2mol/L, be heated to 40 ~ 50 DEG C and stir 2 ~ 3min, then dichloromethane extraction is used, gained organic phase milli-Q water to neutral, namely obtain crude product with anhydrous sodium sulfate drying, filtration, filtrate steaming removal solvent, crude product methylene dichloride dissolves and adds several normal hexane recrystallizations, obtains Propafenone episome, by step (1) gained aqueous phase dissolved, make the sample of 0.1 ~ 15mg/ml, for subsequent use as sample introduction liquid;
(3) high-speed countercurrent chromatography is adopted to split Propafenone: the organic phase obtained with step (1) respectively and aqueous phase are stationary phase and moving phase, countercurrent chromatography separation column is filled up stationary phase, column temperature is 5 ~ 15 DEG C, opening speed controller, rotating speed is 1500 ~ 2000rpm, with the flow velocity of 0.5 ~ 2.0ml/min, moving phase is pumped in post, reach after fluid dynamic equilibrium until two phase solvent system, step (2) sample introduction liquid is by sampling valve sample introduction, detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, collect leading peak elutriant and postpeak elutriant respectively,
(4) leading peak and postpeak elutriant are alkalized to pH11 with 1mol/L sodium hydroxide solution respectively, directly repeatedly extract with methylene dichloride after separating out white powder, combined dichloromethane layer, with saturated common salt water washing dichloromethane layer to neutral, with anhydrous sodium sulfate drying, steam to desolventize after filtering and namely obtain left-handed Propafenone and dextrorotation Propafenone crude product respectively, add normal hexane recrystallization after dissolving crude product with methylene dichloride respectively, obtain left-handed Propafenone and the dextrorotation Propafenone of purifying respectively.
The present invention can adopt analysis mode and semi-preparative counter current chromatograph (analysis mode separator column column volume is 20ml, and semi-preparative separator column column volume is 300ml), and counter current chromatograph is made up of constant flow pump, main frame (separator column), UV-detector, registering instrument etc.
Compared with prior art, beneficial effect of the present invention is mainly reflected in: adopt present method resolving chiral medicine Propafenone can reach higher resolution, and the method is applicable to the preparative counter current chromatograph of various model, can be separated the monomer obtaining left-handed Propafenone and dextrorotation Propafenone.
(4) accompanying drawing explanation
Fig. 1 is the analysis mode high speed adverse current chromatogram figure under embodiment 1 experiment condition;
Fig. 2 is the analysis mode high speed adverse current chromatogram figure under embodiment 4 experiment condition;
Fig. 3 is the analysis mode high speed adverse current chromatogram figure under embodiment 5 experiment condition;
Fig. 4 is the analysis mode high speed adverse current chromatogram figure under embodiment 8 experiment condition;
Fig. 5 is the analysis mode high speed adverse current chromatogram figure under embodiment 9 experiment condition;
Fig. 6 is the semi-preparative high speed adverse current chromatogram figure under embodiment 10 experiment condition;
Fig. 7 is that Fig. 6 middle front part divides the high performance liquid chromatography of (260min ~ 386min) elutriant to detect spectrogram, i.e. S type Propafenone;
Fig. 8 is that the high performance liquid chromatography of Fig. 6 posterior part (398min ~ 554min) elutriant detects spectrogram, i.e. R type Propafenone.
(5) embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Embodiment 1:
Propafenone hydrochloride is converted into Propafenone episome: get 160mg Propafenone hydrochloride, join in the sodium hydroxide solution of 4mL1mol/L, be heated to 50 DEG C and stir 2 ~ 3min, then be transferred in separating funnel and use 20mL dichloromethane extraction 4 times, merging organic phase is also extremely neutral with milli-Q water, anhydrous sodium sulfate drying, steam after filtering and desolventize and obtain Propafenone episome crude product, crude product methylene dichloride dissolves and adds several normal hexane recrystallizations, obtain colourless acicular crystal 121mg, be free Propafenone.
By organic phase: (organic phase is the chloroform containing the positive butyl ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln of 0.05mol/L, pH=3.4, and containing 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take 7.5mg propafenone enantiomers 5ml moving phase to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, rotating speed is 1800rpm, pumps in post with the flow velocity of 0.50ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.79.
Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection (the results are shown in Figure 1) by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is: Chiralcel OD-R column(4.6 × 250mm); Column temperature: 25 DEG C; Moving phase: 0.2mol/L KPF
6: acetonitrile (60:40, v/v) isocratic elution; Flow velocity 0.6ml/min; Determined wavelength 254nm; Sample size: 10 μ l.
Embodiment 2:
By organic phase: (organic phase is the chloroform containing the just own ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln of 0.05mol/L, pH=3.4, and containing 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 7.5mg propafenone enantiomers 5ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, rotating speed is 1800rpm, pumps in post with the flow velocity of 0.50ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.65.Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Embodiment 3:
By organic phase: (organic phase is the methylene dichloride containing the positive butyl ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln pH=3.4 of 0.05mol/L and contains 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 7.5mg propafenone enantiomers 5ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, rotating speed is 1800rpm, pumps in post with the flow velocity of 0.50ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.67.Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Embodiment 4:
By organic phase: (organic phase is the chloroform containing the positive butyl ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln pH=3.4 of 0.05mol/L and contains 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 7.5mg propafenone enantiomers 5ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 5 DEG C, opening speed controller, rotating speed is 1800rpm, pumps in post with the flow velocity of 0.50ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.85.Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection (the results are shown in Figure 2) by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Embodiment 5:
By organic phase: (organic phase is the chloroform containing the positive butyl ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln pH=3.4 of 0.05mol/L and contains 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 7.5mg propafenone enantiomers 5ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, and rotating speed is 1800rpm, pumps in post with the flow velocity of 0.30ml/min by moving phase, reaches after fluid dynamic equilibrium until two phase solvent system, by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.52.Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection (the results are shown in Figure 3) by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Embodiment 6:
By chloroform: (organic phase is the chloroform containing the positive butyl ester of 0.2mol/L L-TARTARIC ACID to water, aqueous phase is the acetic acid/triethylamine buffered soln pH=3.4 of 0.05mol/L and contains 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 7.5mg propafenone enantiomers 5ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, rotating speed is 1800rpm, pumps in post with the flow velocity of 0.50ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.82.Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Embodiment 7:
By organic phase: (organic phase is the chloroform containing the positive butyl ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln pH=3.4 of 0.05mol/L and contains 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 7.5mg propafenone enantiomers 5ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, rotating speed is 1500rpm, pumps in post with the flow velocity of 0.50ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.73.Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Embodiment 8:
By organic phase: (organic phase is the chloroform containing the positive butyl ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln pH=3.4 of 0.05mol/L and contains 0.2mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 7.5mg propafenone enantiomers 5ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, rotating speed is 1800rpm, pumps in post with the flow velocity of 0.50ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.74.Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection (the results are shown in Figure 4) by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Embodiment 9:
By organic phase: (organic phase is the chloroform containing the positive butyl ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln pH=4.35 of 0.05mol/L and contains 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 7.5mg propafenone enantiomers 5ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt analysis mode high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 20ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, rotating speed is 1800rpm, pumps in post with the flow velocity of 0.50ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, calculating resolution is 0.63.Collect leading peak elutriant and postpeak elutriant respectively, carry out high performance liquid phase detection (the results are shown in Figure 5) by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Embodiment 10:
By organic phase: (organic phase is the chloroform containing the positive butyl ester of 0.1mol/L L-TARTARIC ACID to aqueous phase, aqueous phase is the acetic acid/triethylamine buffered soln pH=3.4 of 0.05mol/L and contains 0.1mol/L boric acid) be configured in separating funnel according to the volume ratio of 1:1, shake up rear stratification.After ready to balance for some time, will separate mutually up and down, organic phase is as stationary phase, and aqueous phase is as moving phase.Take the 91.6mg propafenone enantiomers 15ml moving phase obtained in embodiment 1 to dissolve, make sample solution after dissolving stand-by.
Adopt semi-preparative high-speed counter-current chromatograph to split propafenone enantiomers, separator column volume is 300ml.Before sample introduction, countercurrent chromatography separation column is filled up stationary phase, column temperature is 15 DEG C, opening speed controller, rotating speed is 800rpm, pumps in post with the flow velocity of 2.00ml/min by moving phase, reach after fluid dynamic equilibrium until two phase solvent system, sample solution is by sampling valve sample introduction.Then detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, receive leading peak elutriant and postpeak elutriant, calculating resolution is 0.83.Carry out high performance liquid phase detection (the results are shown in Figure 6 ~ 8) by collecting the elutriant obtained, the purity of two monomer elutriants is all greater than 90%.The testing conditions of high performance liquid chromatography is with embodiment 1.
Recovery sample from elutriant: leading peak and postpeak elutriant are alkalized to about pH11 with 1mol/L sodium hydroxide solution respectively, direct 70 ~ 80mL dichloromethane extraction 3 times after separating out a large amount of white powder, combined dichloromethane layer, with saturated common salt water washing dichloromethane layer to neutral, with anhydrous sodium sulfate drying, steam after filtering and desolventize and obtain left-handed Propafenone and dextrorotation Propafenone, add several normal hexane recrystallizations after finally dissolving crude product with methylene dichloride, obtain the left-handed Propafenone of 20mg ~ 25mg and 20mg ~ 25mg dextrorotation Propafenone of purifying respectively.
Claims (2)
1. a Propafenone drug enantiomer method for splitting, described method comprises:
(1) organic solvent containing L-TARTARIC ACID ester and the acetic acid/triethylamine buffer solution containing boric acid are mixed according to volume ratio 1:1, stratification, be separated and obtain organic phase and aqueous phase, for subsequent use; In described organic solvent, the concentration of L-TARTARIC ACID ester is 0.02 ~ 0.5mol/L; The pH of described acetic acid/triethylamine buffer solution containing boric acid is 2.0 ~ 5.0, and the concentration of its mesoboric acid is 0.01 ~ 0.30mol/L; Described organic solvent is one of following or wherein two or more mixture: chloroform, methylene dichloride, toluene, chlorobenzene, normal hexane, normal heptane, Skellysolve A, hexanaphthene, sherwood oil, ether, methyl tertiary butyl ether; Described L-TARTARIC ACID ester is one of following: the just own ester of L-TARTARIC ACID, the positive butyl ester of L-TARTARIC ACID;
(2) Propafenone hydrochloride is converted into Propafenone episome, and by step (1) gained aqueous phase dissolved, makes the sample of 0.1 ~ 15mg/ml, for subsequent use as sample introduction liquid;
(3) high-speed countercurrent chromatography is adopted to split Propafenone: the organic phase obtained with step (1) respectively and aqueous phase are stationary phase and moving phase, countercurrent chromatography separation column is filled up stationary phase, column temperature is 5 ~ 30 DEG C, opening speed controller, rotating speed is 500 ~ 2000rpm, with the flow velocity of 0.2 ~ 3.0ml/min, moving phase is pumped in post, reach after fluid dynamic equilibrium until two phase solvent system, step (2) sample introduction liquid is by sampling valve sample introduction, detect with the UV-detector of wavelength 190 ~ 400nm, according to ultraviolet detection spectrogram, collect leading peak elutriant and postpeak elutriant respectively,
(4) from step (3), collect recovery in the leading peak elutriant obtained and postpeak elutriant respectively obtain the monomer of left-handed Propafenone and dextrorotation Propafenone.
2. the method for claim 1, is characterized in that described method is as follows:
(1) chloroform containing the positive butyl ester of L-TARTARIC ACID and the acetic acid/triethylamine buffer solution containing boric acid are mixed according to volume ratio 1:1, stratification, be separated and obtain organic phase and aqueous phase, for subsequent use; In described chloroform, the concentration of L-TARTARIC ACID ester is 0.1 ~ 0.2mol/L; The pH of described acetic acid/triethylamine buffer solution containing boric acid is 2.0 ~ 4.0, and the concentration of its mesoboric acid is 0.1 ~ 0.2mol/L;
(2) getting Propafenone hydrochloride joins in the sodium hydroxide solution of 1 ~ 2mol/L, be heated to 40 ~ 50 DEG C and stir 2 ~ 3min, then dichloromethane extraction is used, gained organic phase milli-Q water to neutral, namely obtain crude product with anhydrous sodium sulfate drying, filtration, filtrate steaming removal solvent, crude product methylene dichloride dissolves and adds several normal hexane recrystallizations, obtain Propafenone episome, by step (1) gained aqueous phase dissolved, make the sample of 0.1 ~ 15mg/ml, for subsequent use as sample introduction liquid;
(3) high-speed countercurrent chromatography is adopted to split Propafenone: the organic phase obtained with step (1) respectively and aqueous phase are stationary phase and moving phase, countercurrent chromatography separation column is filled up stationary phase, column temperature is 5 ~ 15 DEG C, opening speed controller, rotating speed is 1500 ~ 2000rpm, with the flow velocity of 0.5 ~ 2.0ml/min, moving phase is pumped in post, reach after fluid dynamic equilibrium until two phase solvent system, step (2) sample introduction liquid is by sampling valve sample introduction, detect with the UV-detector of wavelength 254nm, according to ultraviolet detection spectrogram, collect leading peak elutriant and postpeak elutriant respectively,
(4) leading peak and postpeak elutriant are alkalized to pH11 with 1mol/L sodium hydroxide solution respectively, directly repeatedly extract with methylene dichloride after separating out white powder, combined dichloromethane layer, with saturated common salt water washing dichloromethane layer to neutral, with anhydrous sodium sulfate drying, steam to desolventize after filtering and namely obtain left-handed Propafenone and dextrorotation Propafenone crude product respectively, add normal hexane recrystallization after dissolving crude product with methylene dichloride respectively, obtain left-handed Propafenone and the dextrorotation Propafenone of purifying respectively.
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