CN103193572A - Separation method of single enantiomer of pantoprazole compound - Google Patents
Separation method of single enantiomer of pantoprazole compound Download PDFInfo
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- CN103193572A CN103193572A CN2013101183490A CN201310118349A CN103193572A CN 103193572 A CN103193572 A CN 103193572A CN 2013101183490 A CN2013101183490 A CN 2013101183490A CN 201310118349 A CN201310118349 A CN 201310118349A CN 103193572 A CN103193572 A CN 103193572A
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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 Omprazole compound single enantiomer.
Background technology
Proton pump inhibitor is to treat the state-of-the-art class medicine of peptide ulceration at present, and it reaches rapid healing ulcer by the secretion of efficient gastric acid inhibitory fast and removing Hp.Wherein, drawing the azole proton pump inhibitor to be one is the sulfoxide of chiral centre with the sulphur atom, by the left-handed racemic modification of forming with enantiomorph dextrorotation.In recent years, find by the research contrast, single enantiomer draw the azole proton pump inhibitor as (S)-omeprazole, (R)-lansoprazole, (S)-pantoprazole and (R)-rabeprazole, its drug effect is than its racemize height, and toxic side effect is little, so the single enantiomer of preparation Omprazole compound is particularly important in pharmaceutical industry.
Separation method for the Omprazole compound single enantiomer mainly contains mechanical Split Method, chemical resolution method, biological chemistry Split Method, extraction Split Method etc. at present.
The machinery Split Method is for a racemic mixture, its two kinds of enantiomorphs are often spontaneously separated out respectively with macroscopical crystal, if these crystal can with the naked eye distinguish, so just can be under the help of magnifying glass, instrument with tweezers and so on is sorted out them separately, thereby reaches the purpose of fractionation.But the shortcoming of mechanical Split Method is too loaded down with trivial details, can not be applied to racemic compound and racemic solid solution.
Chemical resolution method is to utilize chiral reagent and racemic modification reaction, generate two diastereomers, the difference of their physical propertiess of recycling (as solubleness, vapour pressure, absorption system etc.) splits it, these two diastereomers is restored respectively at last to be original enantiomorph again.But this method reactions steps is long, yield is low, and resolving agent is expensive usually.
When the biological chemistry Split Method referred to that certain micro-organisms and mould grow in the dilute solution of racemic modification, the speed of destroying a kind of enantiomorph wherein was faster than another kind, thereby reached the purpose of fractionation.The biological chemistry Split Method can extract enzyme as biological catalyst with complete microorganism cells or from microorganism.Bacterial screening difficulty, zymin are difficult for preserving, the product postprocessing workload can only obtain shortcomings such as a kind of enantiomorph greatly and usually but biological Split Method also has.
The extraction Split Method is the fractionation that traditional solvent extraction technology is applied to racemic modification, compares with traditional solvent extraction technology, and except racemic modification to be split, two liquid phases that contact with each other have at least one mutually opticity will be arranged.But this method extraction purity is lower, and the extraction process complexity.
But adopt the purity of single enantiomer of the Omprazole compound that above-mentioned separation method obtains lower, therefore, development along with chromatographic technique, the chromatogram Split Method becomes a kind of main method of separating Omprazole compound gradually, and this method is simple and efficient and single enantiomer purity that separation obtains is higher.The chromatogram Split Method is to adopt stationary phase or moving phase with chirality that the Omprazole compound single enantiomer is separated, the patent No. is the proton pump inhibitor that the United States Patent (USP) of US2005/0049282 adopts the chromatographic separation chirality, this patent adopts simulation moving-bed bed chromatogram, with material with chirality as stationary phase, successful separation omeprazole, pantoprazole, lansoprazole, the single enantiomer of Omprazole compounds such as rabeprazole, but this 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 to provide a kind of separation method of Omprazole compound single enantiomer, and the separation method cost of single enantiomer provided by the present invention is low.
The invention provides a kind of separation method of Omprazole compound single enantiomer, may further comprise the steps:
Adopt silica gel column chromatography, as moving phase the mixture of Omprazole compound enantiomorph is carried out wash-out with organic solvent, obtain the Omprazole compound single enantiomer;
Described organic solvent is one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene.
Preferably, the order number of silica gel is 200～300 orders or 300～400 orders in the described silica gel column chromatography.
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 ℃.
Preferably, the mass ratio of the mixture of described Omprazole compound enantiomorph and the silica gel in the 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 the silica gel column chromatography as follows:
The mixture of described Omprazole compound enantiomorph is mixed with organic solvent, add silica gel, stir, obtain mixed gel;
Described mixed gel is carried out covering after the drying surface of the silica gel of described silica gel column chromatography.
Compared with prior art, the present invention adopts silica gel column chromatography, as moving phase the mixture of Omprazole compound enantiomorph is carried out wash-out with organic solvent, obtains the Omprazole compound single enantiomer; Described organic solvent is one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene.The present invention with silica gel as stationary phase, organic solvent carries out wash-out as moving phase to the mixture of Omprazole compound enantiomorph, wherein, with one or more organic solvents in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene as moving phase when the enantiomorph in the Omprazole compound is carried out wash-out, Omprazole compound exists with the form of dimer or oligomer in above-mentioned organic solvent, along with elutriant is at first come out by wash-out, thereby reach separation to the Omprazole compound single enantiomer.The present invention adopts silica gel as stationary phase,, has reduced and has adopted the chromatogram Split Method to separate the cost of Omprazole compound single enantiomer as moving phase with organic solvent common to those skilled in the art.
Description of drawings
Fig. 1 is the liquid chromatogram of the esomeprazole of embodiment 1 separation;
Fig. 2 is the liquid chromatogram of omeprazole standard substance;
Fig. 3 is the liquid chromatogram of the esomeprazole of 88.4%ee for optical purity.
Embodiment
The invention provides a kind of separation method of Omprazole compound single enantiomer, may further comprise the steps:
Adopt silica gel column chromatography, as moving phase the mixture of Omprazole compound enantiomorph is carried out wash-out with organic solvent, obtain the Omprazole compound single enantiomer;
Described organic solvent is one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene.
The present invention adopts silica gel column chromatography that the mixture of Omprazole compound enantiomorph is separated, the present invention there is no particular restriction to the source of described silica gel column chromatography, can get final product for chromatography column well known to those skilled in the art, described chromatography column can also can be pressurizing chromatographic column for the normal pressure chromatography 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, more preferably 40～50mm; The height of described chromatography column is preferably 200～1000mm, more preferably 300～600mm.
The present invention there is no particular restriction to the preparation method of described silica gel column chromatography, can adorn post for wet method, also can be dry column-packing, in the present invention, preferably adopts wet method dress post, and concrete grammar is:
Moving phase is packed in the chromatography column, open the piston of described chromatography column lower end, moving phase is slowly reserved, then continuous the pouring in the chromatography column of silica gel, or silica gel mixed with moving phase, making suspension slowly adds in the 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 adds in the chromatography column and keeps certain liquid level, replenishing the loss of the moving phase that flows out in the chromatography column, until silica gel being added and till sedimentation no longer changes in post.
In the present invention, the used filler of silica gel column chromatography is silica gel, and the present invention there is no particular restriction to described silica gel, and silica gel column chromatography well known in the art gets final product with silica gel, the particle diameter of described silica gel is preferably 200～300 orders or 300～400 orders, more preferably 300～400 orders.The consumption of described silica gel is as the criterion with the volume of chromatography column, is about to join in the chromatography column after the abundant swelling of described silica gel, and the distance of the upper surface of silica gel and chromatography column upper end outlet is preferably 0.5～2cm in the chromatography column, more preferably 1～2cm.
The moving phase of filling silica gel column chromatography of the present invention is the organic solvent of the mixture of wash-out Omprazole compound enantiomorph, described organic solvent is preferably one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene, more preferably one or more of methyl tertiary butyl ether, ethyl acetate and sherwood oil.The present invention there is no particular restriction to the source of described organic solvent, general commercially available getting final product.
After silica gel column chromatography fills, the mixture of described Omprazole compound enantiomorph is placed the surface of silica gel column chromatography, carry out wash-out.In the present invention, for sample on the mixture of described Omprazole compound enantiomorph is even, preferred as follows the mixture of described Omprazole compound enantiomorph is placed silica gel column chromatography:
The mixture of described Omprazole compound enantiomorph is mixed with organic solvent, add silica gel, stir, obtain mixed gel;
Described mixed gel is carried out covering after the drying surface of the silica gel of described silica gel column chromatography.
The present invention mixes the mixture of Omprazole compound enantiomorph with organic solvent, obtain 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 is preferably one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene, one or more of methyl tertiary butyl ether, ethyl acetate and sherwood oil.The present invention there is no particular restriction to the source of described organic solvent, general commercially available getting final product.
The present invention adds silica gel in mixing solutions, stir, and obtains mixed gel, and the mixture of described Omprazole compound enantiomorph and the mass ratio of described silica gel are 1:(5～10), 1:(6～8 more preferably).
The mixed gel that obtains is carried out drying, cover the silica gel surface of described silica gel column chromatography.The present invention there is no particular restriction to described mixed gel drying mode, and drying mode well known to those skilled in the art gets final product.
Behind sample on the mixture of described Omprazole compound enantiomorph, as moving phase the mixture of Omprazole compound enantiomorph is carried out wash-out with organic solvent, obtain the Omprazole compound single enantiomer.Described organic solvent is preferably one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene, 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, more preferably (5～8): 1.The present invention there is no particular restriction to the source of described organic solvent, general commercially available getting final product.The pressure of described wash-out is preferably 1～4MPa, more preferably 2～3MPa; The temperature of described wash-out is preferably 22～28 ℃, more preferably 24～27 ℃.
When the present invention carries out wash-out as moving phase with the mixture of Omprazole compound enantiomorph with organic solvent, end at described silica gel column chromatography receives elutriant, solution that will wash-out goes out from chromatography column with capillary glass microcap point on silica-gel plate, under ultraviolet lamp, detect, when point sample when silica-gel plate presents the point of purple, then showing has the sample wash-out to come out, receive described elutriant, described elutriant contiguous segmentation is received, the hop count of described reception is preferably 25～80 sections, and more preferably 30～60 sections, every section elutriant places receiving vessel, the volume of described every section elutriant is preferably 20～40mL, more preferably 25～35mL.Measure the optical purity of the elutriant in the described receiving vessel respectively by high performance liquid chromatography, merging optical purity is the elutriant of 100%ee, can obtain the Omprazole compound single enantiomer.The used preferred model of chromatographic column of the high performance liquid chromatography of described detection elutriant optical purity is that CHIRALPAKAD-H, specification are 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 with silica gel as stationary phase, organic solvent carries out wash-out as moving phase to the mixture of Omprazole compound enantiomorph, wherein, with one or more organic solvents in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene as moving phase when the enantiomorph in the Omprazole compound is carried out wash-out, Omprazole compound exists with the form of dimer or oligomer in above-mentioned organic solvent, along with elutriant is at first come out by wash-out, thereby reach separation to the Omprazole compound single enantiomer.The present invention adopts silica gel as stationary phase,, has reduced and has adopted the chromatogram Split Method to separate the cost of Omprazole compound single enantiomer as moving phase with organic solvent common to those skilled in the art.
In order further to understand the present invention, below in conjunction with embodiment the separation method of Omprazole compound single enantiomer provided by the invention is described, protection scope of the present invention is not limited by the following examples.Embodiment 1
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 88.4%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 88.4%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 32 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～8 bottle is the esomeprazole of 100%ee for optical purity, according to the optical purity of the esomeprazole after 1～8 bottle of merging of condition determination mensuration of above-mentioned high performance liquid chromatography, the results are shown in Figure 1, Fig. 1 is the liquid chromatogram of the esomeprazole of embodiment 1 separation.Wherein, 1 is that left-handed omeprazole is 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 high-efficient liquid phase chromatogram of the esomeprazole of embodiment 1 preparation.
Table 1 is the analytical results of high-efficient liquid phase chromatogram of the esomeprazole of embodiment 1 preparation
By Fig. 1 and table 1 as can be known, optical purity is 100%ee in the esomeprazole after 1～8 bottle of merging.
Described 1～8 bottle of optical purity esomeprazole that is 100%ee merged and evaporate to dryness gets the esomeprazole of 0.26g100%ee, merge the esomeprazole that evaporates to dryness get 0.39g88%ee with 9～20 bottles, merge the esomeprazole that evaporates to dryness get 0.33g70%ee with 21～32 bottles.
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The left pantoprazole that with the 1g optical purity is 82%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the left pantoprazole of 82%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 38 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 290nm.
Wherein, 1～6 bottle is the left pantoprazole of 100%ee for optical purity, merge and evaporate to dryness gets the esomeprazole of 0.14g100%ee, merge the left pantoprazole that evaporates to dryness get 0.3g90%ee with 7～15 bottles, merge the left pantoprazole that evaporates to dryness get 0.55g75%ee with 16～38 bottles.
Embodiment 3
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The R-lansoprazole that with the 1g optical purity is 81%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the R-lansoprazole of 81%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 30 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 285nm.
Wherein, 1～3 bottle is the R-lansoprazole of 100%ee for optical purity, merge and evaporate to dryness gets the R-lansoprazole of 0.09g100%ee, merge the R-lansoprazole that evaporates to dryness get 0.35g94%ee with 4～15 bottles, merge the R-lansoprazole that evaporates to dryness get 0.55g71%ee with 16～30 bottles.
Embodiment 4
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The right rabeprazole that with the 1g optical purity is 80%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the right rabeprazole of 80%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 28 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 270nm.
Wherein, 1～2 bottle is the right rabeprazole of 100%ee for optical purity, merge and evaporate to dryness gets the right rabeprazole of 0.05g100%ee, merge the right rabeprazole that evaporates to dryness get 0.4g90%ee with 3～15 bottles, merge the right rabeprazole that evaporates to dryness get 0.55g71%ee with 16～28 bottles.
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 96%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 96%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 33 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～18 bottle for optical purity is the esomeprazole of 100%ee, merges and evaporate to dryness gets the esomeprazole of 0.49g100%ee, merges the esomeprazole that evaporates to dryness get 0.51g92%ee with 19～33 bottles.
Embodiment 6
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 66%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 66%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 34 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～5 bottle for optical purity is the esomeprazole of 100%ee, merges and evaporate to dryness gets the esomeprazole of 0.13g100%ee, merges the esomeprazole that evaporates to dryness get 0.87g63%ee with 6～34 bottles.
Embodiment 7
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 30%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 66%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 34 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～5 bottle for optical purity is the esomeprazole of 100%ee, merges and evaporate to dryness gets the esomeprazole of 0.13g46%ee, merges the esomeprazole that evaporates to dryness get 0.87g28%ee with 6～34 bottles.
By the result as can be known, the separation method that the Omprazole compound single enantiomer that provides is provided in the present invention can be used for the enrichment of Omprazole compound mixture of enantiomers, by method provided by the present invention, can improve the optical purity of the lower Omprazole compound mixture of enantiomers of optical purity.
Embodiment 8
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 80%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 80%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 40 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～8 bottle is the esomeprazole of 100%ee for optical purity, merge and evaporate to dryness gets the esomeprazole of 0.17g100%ee, merge the esomeprazole that evaporates to dryness get 0.68g80%ee with 9～30 bottles, merge the esomeprazole that evaporates to dryness get 0.15g55%ee with 31～40 bottles.
Embodiment 9
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 80%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 80%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 40 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～8 bottle is the esomeprazole of 100%ee for optical purity, merge and evaporate to dryness gets the esomeprazole of 0.17g100%ee, merge the esomeprazole that evaporates to dryness get 0.68g80%ee with 9～30 bottles, merge the esomeprazole that evaporates to dryness get 0.15g55%ee with 31～40 bottles.
Being 5cm with 90g200～300 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 80%ee mixes with 8g100～200 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 80%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 22 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～2 bottle is the esomeprazole of 100%ee for optical purity, merge and evaporate to dryness gets the esomeprazole of 0.09g100%ee, merge the esomeprazole that evaporates to dryness get 0.56g87%ee with 3～10 bottles, merge the esomeprazole that evaporates to dryness get 0.35g62%ee with 11～22 bottles.
Embodiment 11
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 80%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 80%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 4MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 42 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～8 bottle is the esomeprazole of 100%ee for optical purity, merge and evaporate to dryness gets the esomeprazole of 0.14g100%ee, merge the esomeprazole that evaporates to dryness get 0.57g84%ee with 9～30 bottles, merge the esomeprazole that evaporates to dryness get 0.29g62%ee with 31～48 bottles.
Embodiment 12
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 80%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 80%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 61 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～23 bottle is the esomeprazole of 100%ee for optical purity, merge and evaporate to dryness gets the esomeprazole of 0.34g100%ee, merge the esomeprazole that evaporates to dryness get 0.46g79%ee with 24～40 bottles, merge the esomeprazole that evaporates to dryness get 0.20g48%ee with 41～61 bottles.
Embodiment 13
Being 5cm with 90g300～400 order silica gel diameter of packing into, highly is in the chromatography column of 60cm, obtains silica gel column chromatography;
The esomeprazole that with the 1g optical purity is 80%ee mixes with 8g200～300 purpose silica gel with methylene dichloride dissolving back, after methylene dichloride is removed in decompression, it is evenly covered the surface of silica gel column chromatography;
As moving phase, be that the esomeprazole of 80%ee carry out wash-out separate to optical purity with methyl tertiary butyl ether, described wash-out pressure is 2MPa, and eluting temperature is 25 ℃;
End at silica gel column chromatography receives elutriant, uses capillary glass microcap point on silica-gel plate described elutriant, detects under ultraviolet lamp, after having treated that sample occurs, Erlenmeyer flask with 50mL is collected, and collects 30mL, receives 48 bottles of elutriants that product is arranged altogether for every bottle.
Described elutriant is carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.
Wherein, 1～9 bottle is the esomeprazole of 100%ee for optical purity, merge and evaporate to dryness gets the esomeprazole of 0.19g100%ee, merge the esomeprazole that evaporates to dryness get 0.45g83%ee with 10～30 bottles, merge the esomeprazole that evaporates to dryness get 0.36g66%ee with 31～48 bottles.
Comparative Examples 1
The omeprazole standard substance are carried out high performance liquid phase to be detected, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.Experimental result is seen Fig. 2, and Fig. 2 is the liquid chromatogram of omeprazole standard substance.1 for left-handed omeprazole is esomeprazole, and 2 are 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 Examples 2
Be that the sample to be separated of the esomeprazole of 88.4%ee carries out high performance liquid phase and detects with optical purity among the embodiment 1, selecting model for use is that CHIRALPAK AD-H, specification are 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 the detection wavelength is 280nm.Experimental result is seen Fig. 3, and Fig. 3 is the liquid chromatogram of the esomeprazole of 88.4%ee for optical purity.Wherein, 1 for left-handed omeprazole is esomeprazole, and 2 are the omeprazole of dextrorotation.Be that optical purity is that the liquid chromatogram of the esomeprazole of 88.4%ee carries out integral analysis with described optical purity, the results are shown in Table 3, table 3 is the liquid chromatogram analytical results of the esomeprazole of 88.4%ee for optical purity.
Table 3 is the liquid chromatogram analytical results of the esomeprazole of 88.4%ee for optical purity
By Fig. 1, Fig. 2 and Fig. 3 as can be known, adopt the separation method of Omprazole compound single enantiomer provided by the present invention can obtain the esomeprazole that optical purity is 100%ee.
The result shows that the separation method of Omprazole compound single enantiomer provided by the present invention can reach the separation to the Omprazole compound single enantiomer.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle 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 (10)
1. the separation method of an Omprazole compound single enantiomer may further comprise the steps:
Adopt silica gel column chromatography, as moving phase the mixture of Omprazole compound enantiomorph is carried out wash-out with organic solvent, obtain the Omprazole compound single enantiomer;
Described organic solvent is one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether, sherwood oil, acetone and the toluene.
2. preparation method according to claim 1 is characterized in that, the order number of silica gel is 200～300 orders or 300～400 orders in the described silica gel column chromatography.
3. preparation method according to claim 1 is characterized in that, described organic solvent is one or more of methyl tertiary butyl ether, ethyl acetate and sherwood oil.
4. preparation method according to claim 1 is characterized in that, described organic solvent is the mixing solutions of ethyl acetate and sherwood oil.
5. preparation method according to claim 4 is characterized in that, the volume ratio of described ethyl acetate and sherwood oil is (2～10): 1.
6. preparation method according to claim 1 is characterized in that, the pressure of described wash-out is 1～4MPa.
7. preparation method according to claim 1 is characterized in that, the temperature of described wash-out is 22～28 ℃.
8. preparation method according to claim 1 is characterized in that, the mixture of described Omprazole compound enantiomorph and the mass ratio of the silica gel in the silica gel column chromatography are 1:(50～100).
9. 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.
10. preparation method according to claim 1 is characterized in that, the mixture of described Omprazole compound enantiomorph joins in the silica gel column chromatography as follows:
The mixture of described Omprazole compound enantiomorph is mixed with organic solvent, add silica gel, stir, obtain mixed gel;
Described mixed gel is carried out covering after the drying surface of the silica gel of described silica gel column chromatography.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105457337A (en) * | 2015-11-17 | 2016-04-06 | 重庆臻源红豆杉发展有限公司 | A silica gel loading and sample loading method of a chromatographic column |
| CN106928190A (en) * | 2015-12-29 | 2017-07-07 | 中美华世通生物医药科技（武汉）有限公司 | The method that Lansoprazole is prepared using SMBC separation |
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| US20050049282A1 (en) * | 2001-12-18 | 2005-03-03 | Astrazeneca Ab | Process |
| CN1950364A (en) * | 2004-03-12 | 2007-04-18 | 弗特克斯药品有限公司 | Processes and intermediates for the preparation of aspartic acetal caspase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050049282A1 (en) * | 2001-12-18 | 2005-03-03 | Astrazeneca Ab | Process |
| CN1950364A (en) * | 2004-03-12 | 2007-04-18 | 弗特克斯药品有限公司 | Processes and intermediates for the preparation of aspartic acetal caspase inhibitors |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105457337A (en) * | 2015-11-17 | 2016-04-06 | 重庆臻源红豆杉发展有限公司 | A silica gel loading and sample loading method of a chromatographic column |
| CN106928190A (en) * | 2015-12-29 | 2017-07-07 | 中美华世通生物医药科技（武汉）有限公司 | The method that Lansoprazole is prepared using SMBC separation |
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