CN103193572B - Separation method of single enantiomer of pantoprazole compound - Google Patents
Separation method of single enantiomer of pantoprazole compound Download PDFInfo
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- CN103193572B CN103193572B CN201310118349.0A CN201310118349A CN103193572B CN 103193572 B CN103193572 B CN 103193572B CN 201310118349 A CN201310118349 A CN 201310118349A CN 103193572 B CN103193572 B CN 103193572B
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Abstract
The invention provides a separation method of a single enantiomer of a pantoprazole compound. The separation method comprises the following steps of: adopting a silica gel column, and taking an organic solvent as a flowing phase and eluting the mixture of pantoprazole compound enantiomer to obtain the single enantiomer of the pantoprazole compound, wherein the organic solvent is one or more of ethyl acetate, methylene dichloride, methyl tertiary butyl ether, petroleum ether, acetone and toluene. The silica gel is adopted as a fixed phase; and a common organic solvent of technical personnel in the field is taken as a flowing phase. Therefore, the cost of separating the single enantiomer of the pantoprazole compound by a chromatographic separation method is reduced.
Description
Technical field
The invention belongs to separation technology field, be specifically related to a kind of separation method of single enantiomer of pantoprazole compound.
Background technology
Proton pump inhibitor treats the state-of-the-art class medicine of peptide ulceration at present, and it reaches rapid healing ulcer by efficient gastric acid secretion inhibiting fast and removing Hp.Wherein, draw azole proton pump inhibitor to be one with sulphur atom to be the sulfoxide of chiral centre, the racemic modification be made up of left-handed and enantiomorph that is dextrorotation.In recent years, found by investigation and comparison, single enantiomer draw azole proton pump inhibitor as (S)-omeprazole, (R)-lansoprazole, (-)-pantoprazole and (R)-rabeprazole, its drug effect is than its racemize height, and toxic side effect is little, so prepare the single enantiomer of Omprazole compound, particularly important in pharmaceutical industry.
Separation method at present for single enantiomer of pantoprazole compound mainly contains physical separation, chemical resolution method, biological chemistry Split Method, Extraction resolution method etc.
Physical separation is for a racemic mixture, its two kinds of enantiomorphs are often spontaneously separated out with macroscopical crystal respectively, if these crystal can with the naked eye be distinguished, and so just can under the help of magnifying glass, with the instrument of tweezers and so on, they are sorted out separately, thus reach the object of fractionation.But the shortcoming of physical separation is too loaded down with trivial details, can not be applied to racemic compound and racemic solid solution.
Chemical resolution method utilizes chiral reagent and racemic modification to react, generate two diastereomers, recycle the difference of their physical propertiess (as solubleness, vapour pressure, absorption system etc.), split, finally again these two diastereomers are restored to original enantiomorph respectively.But this method reactions steps is long, yield is low, and usual resolving agent is expensive.
When biological chemistry Split Method refers to that certain micro-organisms and mould grow in the dilute solution of racemic modification, the speed destroying wherein a kind of enantiomorph is faster than another kind, thus reaches the object of fractionation.Biological chemistry Split Method with complete microorganism cells or can extract enzyme as biological catalyst from microorganism.But biological resolution method also has bacterial screening difficulty, zymin is not easily preserved, product postprocessing workload can only obtain the shortcomings such as a kind of enantiomorph greatly and usually.
Extraction resolution method is the fractionation traditional solvent extraction technology being applied to racemic modification, and compared with traditional solvent extraction technology, except racemic modification to be split, two liquid phases contacted with each other have at least a phase to have opticity.But this method extraction purity is lower, and extraction process is complicated.
But the purity of the single enantiomer of the Omprazole compound adopting above-mentioned separation method to obtain is lower, therefore, along with the development of chromatographic technique, Chromatographic resolution method becomes gradually and is separated a kind of main method of Omprazole compound, and the method is simple and efficient and to be separated the single enantiomer purity obtained higher.Chromatographic resolution method adopts to have the stationary phase of chirality or moving phase is separated single enantiomer of pantoprazole compound, the patent No. is the proton pump inhibitor of the United States Patent (USP) employing chromatographic separation chirality of US2005/0049282, this patent adopts simulation moving-bed bed chromatogram, there is the material of chirality as stationary phase, successfully be separated omeprazole, pantoprazole, lansoprazole, the single enantiomer of the Omprazole compounds such as rabeprazole, but the method adopts chiral stationary phase or moving phase, and cost is higher.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is the separation method providing a kind of single enantiomer of pantoprazole compound, and the separation method cost of single enantiomer provided by the present invention is low.
The invention provides a kind of separation method of single enantiomer of pantoprazole compound, comprise the following steps:
Adopt silica gel column chromatography, using organic solvent as moving phase, the mixture of Omprazole compound enantiomorph is carried out wash-out, obtain single enantiomer of pantoprazole compound;
Described organic solvent is one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and toluene.
Preferably, in described silica gel column chromatography, the order number of silica gel is 200 ~ 300 orders or 300 ~ 400 orders.
Preferably, described organic solvent is one or more of methyl tertiary butyl ether, ethyl acetate and sherwood oil.
Preferably, described organic solvent is the mixing solutions of ethyl acetate and sherwood oil.
Preferably, the volume ratio of described ethyl acetate and sherwood oil is (2 ~ 10): 1.
Preferably, the pressure of described wash-out is 1 ~ 4MPa.
Preferably, the temperature of described wash-out is 22 ~ 28 DEG C.
Preferably, the mass ratio of the silica gel in the mixture of described Omprazole compound enantiomorph and silica gel column chromatography is 1:(50 ~ 100).
Preferably, the optical purity of the mixture of described Omprazole compound enantiomorph is 65%ee ~ 99%ee.
Preferably, the mixture of described Omprazole compound enantiomorph joins in silica gel column chromatography as follows:
The mixture of described Omprazole compound enantiomorph is mixed with organic solvent, adds silica gel, stir, obtain mixed gel;
The surface of the silica gel of described silica gel column chromatography is covered after described mixed gel is carried out drying.
Compared with prior art, the present invention adopts silica gel column chromatography, using organic solvent as moving phase, the mixture of Omprazole compound enantiomorph is carried out wash-out, obtains single enantiomer of pantoprazole compound; Described organic solvent is one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and toluene.The present invention is using silica gel as stationary phase, organic solvent carries out wash-out as moving phase to the mixture of Omprazole compound enantiomorph, wherein, using one or more organic solvents in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and toluene as moving phase when carrying out wash-out to the enantiomorph in Omprazole compound, Omprazole compound exists with the form of dimer or oligomer in above-mentioned organic solvent, along with elutriant first by wash-out out, thus reach the separation to single enantiomer of pantoprazole compound.The present invention adopts silica gel as stationary phase, using organic solvent common to those skilled in the art as moving phase, reduces the cost adopting Chromatographic resolution method to be separated single enantiomer of pantoprazole compound.
Accompanying drawing explanation
Fig. 1 is the liquid chromatogram of the esomeprazole that embodiment 1 is separated;
Fig. 2 is the liquid chromatogram of omeprazole standard substance;
The liquid chromatogram of Fig. 3 to be optical purity be esomeprazole of 88.4%ee.
Embodiment
The invention provides a kind of separation method of single enantiomer of pantoprazole compound, comprise the following steps:
Adopt silica gel column chromatography, using organic solvent as moving phase, the mixture of Omprazole compound enantiomorph is carried out wash-out, obtain single enantiomer of pantoprazole compound;
Described organic solvent is one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and toluene.
The present invention adopts the mixture of silica gel column chromatography to Omprazole compound enantiomorph to be separated, the source of the present invention to described silica gel column chromatography there is no particular restriction, it can be chromatography column well known to those skilled in the art, described chromatography column can be normal pressure chromatography column also can be pressurizing chromatographic column, in the present invention, in order to improve separating effect, preferably adopt pressurizing chromatographic column.The internal diameter of described chromatography column is preferably 25 ~ 80mm, is more preferably 40 ~ 50mm; The height of described chromatography column is preferably 200 ~ 1000mm, is more preferably 300 ~ 600mm.
The preparation method of the present invention to described silica gel column chromatography there is no particular restriction, and can be wet method dress post, also can be dry column-packing, and in the present invention, preferably adopt wet method dress post, concrete grammar is:
Moving phase is loaded in chromatography column, open the piston of described chromatography column lower end, moving phase is slowly reserved, then silica gel continuous print is poured in chromatography column, or silica gel is mixed with moving phase, make suspension slowly to add in chromatography column, silica gel relies on drive free setting in chromatography column of gravity and moving phase, in the process of dress post, moving phase constantly to add in chromatography column and keeps certain liquid level, with the loss of the moving phase flowed out in supplementary chromatography column, until silica gel to be added and till in post, sedimentation no longer changes.
In the present invention, silica gel column chromatography filler used is silica gel, and the present invention there is no particular restriction to described silica gel, silica gel column chromatography silica gel well known in the art, the particle diameter of described silica gel is preferably 200 ~ 300 orders or 300 ~ 400 orders, is more preferably 300 ~ 400 orders.The consumption of described silica gel is as the criterion with the volume of chromatography column, joins in chromatography column after fully swelling by described silica gel, and in chromatography column, the upper surface of silica gel and the distance of chromatography column upper end outlet are preferably 0.5 ~ 2cm, are more preferably 1 ~ 2cm.
The organic solvent of the moving phase of filling silica gel column chromatography of the present invention and the mixture of wash-out Omprazole compound enantiomorph, described organic solvent be preferably in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and toluene one or more, be more preferably one or more of methyl tertiary butyl ether, ethyl acetate and sherwood oil.The source of the present invention to described organic solvent there is no particular restriction, generally commercially available.
After silica gel column chromatography fills, the mixture of described Omprazole compound enantiomorph is placed in the surface of silica gel column chromatography, carries out wash-out.In the present invention, in order to the mixture loading of described Omprazole compound enantiomorph is even, preferably as follows the mixture of described Omprazole compound enantiomorph is placed in silica gel column chromatography:
The mixture of described Omprazole compound enantiomorph is mixed with organic solvent, adds silica gel, stir, obtain mixed gel;
The surface of the silica gel of described silica gel column chromatography is covered after described mixed gel is carried out drying.
The mixture of Omprazole compound enantiomorph mixes with organic solvent by the present invention, obtains mixing solutions, and in the present invention, the optical purity of the mixture of described Omprazole compound enantiomorph is preferably 65%ee ~ 99%ee.Described organic solvent is the moving phase of filling silica gel column chromatography, described organic solvent be preferably in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and toluene one or more, one or more of methyl tertiary butyl ether, ethyl acetate and sherwood oil.The source of the present invention to described organic solvent there is no particular restriction, generally commercially available.
The present invention adds silica gel in mixing solutions, stirs, and obtains mixed gel, and the mixture of described Omprazole compound enantiomorph and the mass ratio of described silica gel are 1:(5 ~ 10), be more preferably 1:(6 ~ 8).
The mixed gel obtained is carried out drying, covers the Silica Surface of described silica gel column chromatography.The present invention there is no particular restriction to described mixed gel drying mode, drying mode well known to those skilled in the art.
After the mixture loading of described Omprazole compound enantiomorph, using organic solvent as moving phase, the mixture of Omprazole compound enantiomorph is carried out wash-out, obtain single enantiomer of pantoprazole compound.Described organic solvent be preferably in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and toluene one or more, one or more of methyl tertiary butyl ether, ethyl acetate and sherwood oil, most preferably be methyl tertiary butyl ether, or the mixing solutions of ethyl acetate and sherwood oil, wherein, in the mixing solutions of described ethyl acetate and sherwood oil, the volume ratio of ethyl acetate and sherwood oil is preferably (2 ~ 10): 1, is more preferably (5 ~ 8): 1.The source of the present invention to described organic solvent there is no particular restriction, generally commercially available.The pressure of described wash-out is preferably 1 ~ 4MPa, is more preferably 2 ~ 3MPa; The temperature of described wash-out is preferably 22 ~ 28 DEG C, is more preferably 24 ~ 27 DEG C.
When the mixture of Omprazole compound enantiomorph is carried out wash-out using organic solvent as moving phase by the present invention, elutriant is received at the end of described silica gel column chromatography, by the solution capillary glass microcap point that elutes from chromatography column on silica-gel plate, detect under ultraviolet lamp, when point sample presents the point of purple on silica-gel plate, then show have sample elution out, receive described elutriant, described elutriant contiguous segmentation is received, the hop count of described reception is preferably 25 ~ 80 sections, be more preferably 30 ~ 60 sections, every section of elutriant is placed in receiving vessel, the volume of described every section of elutriant is preferably 20 ~ 40mL, be more preferably 25 ~ 35mL.Measured the optical purity of the elutriant in described receiving vessel respectively by high performance liquid chromatography, merging optical purity is the elutriant of 100%ee, can obtain single enantiomer of pantoprazole compound.The preferred model of chromatographic column that the high performance liquid chromatography of described detection elutriant optical purity is used is CHIRALPAKAD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, and described moving phase is preferably the mixing solutions of normal hexane and ethanol or the mixing solutions of normal hexane and Virahol.
The present invention is using silica gel as stationary phase, organic solvent carries out wash-out as moving phase to the mixture of Omprazole compound enantiomorph, wherein, using one or more organic solvents in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and toluene as moving phase when carrying out wash-out to the enantiomorph in Omprazole compound, Omprazole compound exists with the form of dimer or oligomer in above-mentioned organic solvent, along with elutriant first by wash-out out, thus reach the separation to single enantiomer of pantoprazole compound.The present invention adopts silica gel as stationary phase, using organic solvent common to those skilled in the art as moving phase, reduces the cost adopting Chromatographic resolution method to be separated single enantiomer of pantoprazole compound.
In order to understand the present invention further, be described below in conjunction with the separation method of embodiment to single enantiomer of pantoprazole compound provided by the invention, protection scope of the present invention is not limited by the following examples.Embodiment 1
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 88.4%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 88.4%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 32 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.
Wherein, 1 ~ 8 bottle for optical purity be the esomeprazole of 100%ee, measure the optical purity of the esomeprazole after 1 ~ 8 bottle of merging according to the condition determination of above-mentioned high performance liquid chromatography, the results are shown in Figure the liquid chromatogram that 1, Fig. 1 is the esomeprazole that embodiment 1 is separated.Wherein, 1 is left-handed omeprazole and esomeprazole.The liquid chromatogram of described esomeprazole is carried out integral analysis, the results are shown in Table 1, table 1 is the analytical results of the high-efficient liquid phase chromatogram of esomeprazole prepared by embodiment 1.
Table 1 is the analytical results of the high-efficient liquid phase chromatogram of esomeprazole prepared by embodiment 1
From Fig. 1 and table 1, in the esomeprazole after 1 ~ 8 bottle of merging, optical purity is 100%ee.
By described 1 ~ 8 bottle of optical purity be that the esomeprazole of 100%ee merges and evaporate to dryness obtains the esomeprazole of 0.26g100%ee, merge 9 ~ 20 bottles the esomeprazole that evaporate to dryness obtains 0.39g88%ee, merge 21 ~ 32 bottles the esomeprazole that evaporate to dryness obtains 0.33g70%ee.
Embodiment 2
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography after the left pantoprazole methylene dichloride dissolving of 82%ee;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the left pantoprazole that optical purity is 82%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 38 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 50:50, and determined wavelength is 290nm.
Wherein, 1 ~ 6 bottle for optical purity be the left pantoprazole of 100%ee, merge also evaporate to dryness and obtain the esomeprazole of 0.14g100%ee, merge 7 ~ 15 bottles the left pantoprazole that evaporates to dryness obtain 0.3g90%ee, merge 16 ~ 38 bottles the left pantoprazole that evaporates to dryness obtain 0.55g75%ee.
Embodiment 3
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the R-lansoprazole methylene dichloride dissolving of 81%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the R-lansoprazole that optical purity is 81%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 30 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 50:50, and determined wavelength is 285nm.
Wherein, 1 ~ 3 bottle for optical purity be the R-lansoprazole of 100%ee, merge also evaporate to dryness and obtain the R-lansoprazole of 0.09g100%ee, merge 4 ~ 15 bottles the R-lansoprazole that evaporates to dryness obtain 0.35g94%ee, merge 16 ~ 30 bottles the R-lansoprazole that evaporates to dryness obtain 0.55g71%ee.
Embodiment 4
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography after the right rabeprazole methylene dichloride dissolving of 80%ee;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the right rabeprazole that optical purity is 80%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 28 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and Virahol, and wherein the volume ratio of normal hexane and Virahol is 80:20, and determined wavelength is 270nm.
Wherein, 1 ~ 2 bottle for optical purity be the right rabeprazole of 100%ee, merge also evaporate to dryness and obtain the right rabeprazole of 0.05g100%ee, merge 3 ~ 15 bottles the right rabeprazole that evaporates to dryness obtain 0.4g90%ee, merge 16 ~ 28 bottles the right rabeprazole that evaporates to dryness obtain 0.55g71%ee.
Embodiment 5
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 96%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 96%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 33 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.
Wherein, 1 ~ 18 bottle for optical purity be the esomeprazole of 100%ee, to merge and evaporate to dryness obtains the esomeprazole of 0.49g100%ee, merge 19 ~ 33 bottles the esomeprazole that evaporates to dryness obtain 0.51g92%ee.
Embodiment 6
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 66%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 66%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 34 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.
Wherein, 1 ~ 5 bottle for optical purity be the esomeprazole of 100%ee, to merge and evaporate to dryness obtains the esomeprazole of 0.13g100%ee, merge 6 ~ 34 bottles the esomeprazole that evaporates to dryness obtain 0.87g63%ee.
Embodiment 7
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 30%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 66%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 34 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.
Wherein, 1 ~ 5 bottle for optical purity be the esomeprazole of 100%ee, to merge and evaporate to dryness obtains the esomeprazole of 0.13g46%ee, merge 6 ~ 34 bottles the esomeprazole that evaporates to dryness obtain 0.87g28%ee.
From result, the separation method that the present invention does the single enantiomer of pantoprazole compound provided may be used for the enrichment of Omprazole compound mixture of enantiomers, by method provided by the present invention, the optical purity of the lower Omprazole compound mixture of enantiomers of optical purity can be improved.
Embodiment 8
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 80%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 80%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 40 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of ethyl acetate and sherwood oil, and wherein the volume ratio of ethyl acetate and sherwood oil is 3:1, and determined wavelength is 280nm.
Wherein, 1 ~ 8 bottle for optical purity be the esomeprazole of 100%ee, merge also evaporate to dryness and obtain the esomeprazole of 0.17g100%ee, merge 9 ~ 30 bottles the esomeprazole that evaporates to dryness obtain 0.68g80%ee, merge 31 ~ 40 bottles the esomeprazole that evaporates to dryness obtain 0.15g55%ee.
Embodiment 9
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 80%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 80%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 40 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of ethyl acetate and methylene dichloride, and wherein the volume ratio of ethyl acetate and methylene dichloride is 2:1, and determined wavelength is 280nm.
Wherein, 1 ~ 8 bottle for optical purity be the esomeprazole of 100%ee, merge also evaporate to dryness and obtain the esomeprazole of 0.17g100%ee, merge 9 ~ 30 bottles the esomeprazole that evaporates to dryness obtain 0.68g80%ee, merge 31 ~ 40 bottles the esomeprazole that evaporates to dryness obtain 0.15g55%ee.
Embodiment 10
It is 5cm that 90g200 ~ 300 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g100 ~ 200 object silica gel after the esomeprazole methylene dichloride dissolving of 80%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 80%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 22 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.
Wherein, 1 ~ 2 bottle for optical purity be the esomeprazole of 100%ee, merge also evaporate to dryness and obtain the esomeprazole of 0.09g100%ee, merge 3 ~ 10 bottles the esomeprazole that evaporates to dryness obtain 0.56g87%ee, merge 11 ~ 22 bottles the esomeprazole that evaporates to dryness obtain 0.35g62%ee.
Embodiment 11
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 80%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 80%ee, described wash-out pressure is 4MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 42 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.
Wherein, 1 ~ 8 bottle for optical purity be the esomeprazole of 100%ee, merge also evaporate to dryness and obtain the esomeprazole of 0.14g100%ee, merge 9 ~ 30 bottles the esomeprazole that evaporates to dryness obtain 0.57g84%ee, merge 31 ~ 48 bottles the esomeprazole that evaporates to dryness obtain 0.29g62%ee.
Embodiment 12
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 80%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 80%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 61 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.
Wherein, 1 ~ 23 bottle for optical purity be the esomeprazole of 100%ee, merge also evaporate to dryness and obtain the esomeprazole of 0.34g100%ee, merge 24 ~ 40 bottles the esomeprazole that evaporates to dryness obtain 0.46g79%ee, merge 41 ~ 61 bottles the esomeprazole that evaporates to dryness obtain 0.20g48%ee.
Embodiment 13
It is 5cm that 90g300 ~ 400 order silica gel is loaded diameter, is highly in the chromatography column of 60cm, obtains silica gel column chromatography;
Be mix 1g optical purity with 8g200 ~ 300 object silica gel after the esomeprazole methylene dichloride dissolving of 80%ee, after decompression removing methylene dichloride, by the surface of its uniform fold at silica gel column chromatography;
Using methyl tertiary butyl ether as moving phase, carry out wash-out separation to the esomeprazole that optical purity is 80%ee, described wash-out pressure is 2MPa, and eluting temperature is 25 DEG C;
Receive elutriant at the end of silica gel column chromatography, by described elutriant capillary glass microcap point on silica-gel plate, detect under ultraviolet lamp, after having sample to occur, collect with the Erlenmeyer flask of 50mL, collect 30mL for every bottle, receive the elutriant that 48 bottles have product altogether.
Described elutriant is carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.
Wherein, 1 ~ 9 bottle for optical purity be the esomeprazole of 100%ee, merge also evaporate to dryness and obtain the esomeprazole of 0.19g100%ee, merge 10 ~ 30 bottles the esomeprazole that evaporates to dryness obtain 0.45g83%ee, merge 31 ~ 48 bottles the esomeprazole that evaporates to dryness obtain 0.36g66%ee.
Comparative example 1
Omeprazole standard substance are carried out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, and wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.Experimental result is shown in Fig. 2, and Fig. 2 is the liquid chromatogram of omeprazole standard substance.1 is left-handed omeprazole and esomeprazole, and 2 is the omeprazole of dextrorotation.The liquid chromatogram of described omeprazole standard substance is carried out integral analysis, the results are shown in Table 2, table 2 is the analytical results of the high performance liquid chromatography of omeprazole standard model.
Table 2 is the analytical results of the high performance liquid chromatography of omeprazole standard model
Comparative example 2
The sample to be separated being the esomeprazole of 88.4%ee by optical purity in embodiment 1 carries out high performance liquid phase detection, select that model is CHIRALPAK AD-H, specification is the chiral chromatographic column of 250mm × 4.6mm, moving phase is the mixing solutions of normal hexane and ethanol, wherein the volume ratio of normal hexane and ethanol is 70:30, and determined wavelength is 280nm.Experimental result is shown in Fig. 3, the liquid chromatogram of Fig. 3 to be optical purity be esomeprazole of 88.4%ee.Wherein, 1 is left-handed omeprazole and esomeprazole, and 2 is the omeprazole of dextrorotation.The liquid chromatogram of to be optical purity by described optical purity the be esomeprazole of 88.4%ee carries out integral analysis, the results are shown in Table 3, table 3 for optical purity be the liquid chromatogram analytical results of the esomeprazole of 88.4%ee.
Table 3 for optical purity be the liquid chromatogram analytical results of the esomeprazole of 88.4%ee
From Fig. 1, Fig. 2 and Fig. 3, adopt the separation method of single enantiomer of pantoprazole compound provided by the present invention to obtain esomeprazole that optical purity is 100%ee.
Result shows, the separation method of single enantiomer of pantoprazole compound provided by the present invention can reach the separation to single enantiomer of pantoprazole compound.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. a separation method for single enantiomer of pantoprazole compound, comprises the following steps:
Adopt silica gel column chromatography, using methyl tertiary butyl ether as moving phase, the mixture of Omprazole compound enantiomorph is carried out wash-out, the pressure of described wash-out is 2 ~ 3MPa, obtains single enantiomer of pantoprazole compound.
2. preparation method according to claim 1, is characterized in that, in described silica gel column chromatography, the order number of silica gel is 200 ~ 300 orders or 300 ~ 400 orders.
3. preparation method according to claim 1, is characterized in that, the temperature of described wash-out is 22 ~ 28 DEG C.
4. preparation method according to claim 1, is characterized in that, the mass ratio of the silica gel in the mixture of described Omprazole compound enantiomorph and silica gel column chromatography is 1:(50 ~ 100).
5. preparation method according to claim 1, is characterized in that, the optical purity of the mixture of described Omprazole compound enantiomorph is 65%ee ~ 99%ee.
6. preparation method according to claim 1, is characterized in that, the mixture of described Omprazole compound enantiomorph joins in silica gel column chromatography as follows:
The mixture of described Omprazole compound enantiomorph is mixed with organic solvent, adds silica gel, stir, obtain mixed gel;
The surface of the silica gel of described silica gel column chromatography is covered after described mixed gel is carried out drying.
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