CN106226426A - A kind of high performance liquid chromatography splits the method for canagliflozin five-membered ring impurity enantiomer - Google Patents
A kind of high performance liquid chromatography splits the method for canagliflozin five-membered ring impurity enantiomer Download PDFInfo
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Abstract
The invention discloses a kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer: raw material five-membered ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 0.1 ~ 25mg/ml；Use high performance liquid chromatograph, with Amylose-type chiral column as chromatographic column, carry out mutually splitting preparation for flowing with the mixed liquor that normal hexane forms with ethanol.The yield that the present invention splits preparation canagliflozin five-membered ring impurity enantiomer is high, and purity can reach more than 98%, is suitable as new drug development reference substance and uses.This method effectively achieves separation and the preparation of R, S configuration in five-membered ring impurity enantiomer, and its separating degree is up to more than 2.6.It is high that high performance liquid chromatography splits automaticity, and preparation efficiency is high.
Description
Technical field
The present invention relates to the fractionation technology of chiral impurity in a kind of medicine, particularly a kind of high performance liquid chromatography splits card lattice
The method arranging clean five-membered ring impurity enantiomer, belongs to pharmaceutical technology field.
Background technology
Canagliflozin (Canagliflozin) is the first SGLT2 inhibitor of FDA approval, is used for treating adult patients
Type ii diabetes, be a kind of white 2(SGLT2 of new sodium glucose co-transporter 2) inhibitor medicaments, by suppression kidney pair
The heavily absorption of glucose, increases glucose excretion, and then reduces the blood sugar level that diabetics has raised.
Owing to must strictly control by-product R, the S-configuration five-membered ring impurity of its building-up process generation in canagliflozin
Content, R, S-configuration five-membered ring mixtures of impurities uses conventional method to be difficult to separate, it is impossible to it is carried out structure elucidation with accurate
Quantitative study, therefore the liquid chromatograph method for splitting of a kind of R, S-configuration five-membered ring impurity of invention is particularly important.
R, S-configuration five-membered ring impurity structural formula is as follows:
。
Summary of the invention
It is an object of the invention to provide a kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer.
The technical scheme that the present invention uses for achieving the above object is as follows: a kind of high performance liquid chromatography splits Ka Gelie
The method of clean five-membered ring impurity enantiomer, is characterized in: raw material five-membered ring impurity mixture of enantiomers is dissolved in organic solvent extremely
Concentration 0.1 ~ 25mg/ml；Use high performance liquid chromatograph, with Amylose-type chiral column as chromatographic column, with normal hexane and ethanol
The mixed liquor of composition carries out for flowing splitting preparation mutually.
The method of institute of the present invention art guest's high performance liquid chromatography fractionation canagliflozin five-membered ring impurity enantiomer: described straight chain
Starch type chiral column is preferably bonded chiral chromatographic column CHIRALPAK IE；Filler preferably Silica Surface is covalently bonded with directly
Chain starch-three (3,5-Dichlorobenzene base carbamate).
One in the preferred dehydrated alcohol of organic solvent described in the inventive method, normal hexane, ethanol, methanol or several
Plant the mixed solvent of composition.The mixture being particularly preferably made up of normal hexane and dehydrated alcohol, and the volume ratio of the two is, just
Hexane: dehydrated alcohol=40 ~ 80: 60 ~ 20, further preferred normal hexane: dehydrated alcohol=60: 40.
In the inventive method, described flow rate of mobile phase is preferably 1.0 ~ 70mL/min, and chromatogram column temperature is preferably 25 ~ 40
DEG C, detection wavelength is preferably 220 ~ 290 nm.Described chromatogram column temperature more preferably 30 ~ 35 DEG C, detection wavelength is further
It is preferably 220 ~ 254 nm.Described sample size is preferably 2 μ L ~ 10mL.
Flowing of the present invention mutually the most by volume percentage calculation, preferably normal hexane: dehydrated alcohol is 40 ~ 80: 60 ~
20, most preferably normal hexane: dehydrated alcohol=60: 40.
In the inventive method, raw material five-membered ring impurity mixture of enantiomers be dissolved in organic solvent to concentration be preferably 5 ~
20mg/ml。
Compared with prior art, the present invention have following technical effect that the present invention split preparation canagliflozin five-membered ring miscellaneous
The yield of matter enantiomer is high, and purity can reach more than 98%, is suitable as new drug development reference substance and uses.The inventive method is effective
Achieve R configuration, the separation of S configuration and preparation in five-membered ring impurity enantiomer, its separating degree is up to more than 2.6.High-efficient liquid
Phase Chromatographic resolution automaticity is high, and preparation efficiency is high.
Accompanying drawing explanation
Fig. 1 is chromatographic isolation result figure in embodiment 6；
Fig. 2 is chromatographic isolation result figure in embodiment 7；
Fig. 3 and Fig. 4 is optical purity testing result figure in embodiment 8.
Detailed description of the invention
Below by being embodied as example and combining accompanying drawing the present invention is expanded on further, but it is not limiting as the present invention.
Embodiment 1, a kind of high performance liquid chromatography splits the method for canagliflozin five-membered ring impurity enantiomer: by raw material five yuan
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 0.1mg/ml；Use high performance liquid chromatograph, with Amylose-type
Chiral column is chromatographic column, carries out mutually splitting preparation with the mixed liquor that normal hexane forms with ethanol for flowing.Described amylose
Type chiral column is bonded chiral chromatographic column CHIRALPAK IE.Described organic solvent is selected from dehydrated alcohol, normal hexane, second
One in alcohol, methanol；Described flow rate of mobile phase is 1.0mL/min, and chromatogram column temperature is 25 DEG C, and detection wavelength is 220nm.
Described sample size is 2 μ L.Flowing the most by volume percentage calculation, normal hexane: dehydrated alcohol is 40:60.
Embodiment 2, a kind of high performance liquid chromatography splits the method for canagliflozin five-membered ring impurity enantiomer: by raw material five yuan
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 25mg/ml；Use high performance liquid chromatograph, with Amylose-type hands
Property post be chromatographic column, the mixed liquor formed with ethanol with normal hexane carries out for flowing splitting preparation mutually.Described Amylose-type
Chiral column is bonded chiral chromatographic column CHIRALPAK IE.Filler preferably Silica Surface is covalently bonded with amylose-three
(3,5-Dichlorobenzene base carbamate).
The mixed solvent of the described organic solvent two kinds of compositions in dehydrated alcohol, normal hexane, ethanol, methanol.Institute
The flow rate of mobile phase stated is 70mL/min, and chromatogram column temperature is 40 DEG C, and detection wavelength is 290 nm.Described sample size is
10mL.Flowing the most by volume percentage calculation, normal hexane: dehydrated alcohol is 80: 20,
Embodiment 3, a kind of high performance liquid chromatography splits the method for canagliflozin five-membered ring impurity enantiomer: by miscellaneous for raw material five-membered ring
Matter mixture of enantiomers is dissolved in organic solvent to concentration 5mg/ml；Use high performance liquid chromatograph, with Amylose-type chiral column
For chromatographic column, carry out mutually splitting preparation with the mixed liquor that normal hexane forms with ethanol for flowing.Described Amylose-type chirality
Post is bonded chiral chromatographic column CHIRALPAK IE.
The mixed solvent of the described organic solvent three kinds of compositions in dehydrated alcohol, normal hexane, ethanol, methanol.
Described flow rate of mobile phase is 10mL/min, and chromatogram column temperature is 30 DEG C, and detection wavelength is 280 nm.Described enters
Sample amount is 1mL.Flowing the most by volume percentage calculation, normal hexane: dehydrated alcohol is 50: 50.
Embodiment 4, a kind of high performance liquid chromatography splits the method for canagliflozin five-membered ring impurity enantiomer: by raw material five yuan
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 20mg/ml；Use high performance liquid chromatograph, with Amylose-type hands
Property post be chromatographic column, the mixed liquor formed with ethanol with normal hexane carries out for flowing splitting preparation mutually.Described Amylose-type
Chiral column is bonded chiral chromatographic column CHIRALPAK IE.
Described organic solvent is the mixture being made up of normal hexane and dehydrated alcohol, and the volume ratio of the two is, just own
Alkane: dehydrated alcohol=60: 40.Described flow rate of mobile phase is 30mL/min, and chromatogram column temperature is 35 DEG C, and detection wavelength is
254nm.Described sample size is 5mL.Flowing the most by volume percentage calculation, normal hexane: dehydrated alcohol=60: 40.
Embodiment 5, a kind of high performance liquid chromatography splits the method for canagliflozin five-membered ring impurity enantiomer: by raw material five yuan
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 1mg/ml；Use high performance liquid chromatograph, with Amylose-type hands
Property post be chromatographic column, the mixed liquor formed with ethanol with normal hexane carries out for flowing splitting preparation mutually.Described Amylose-type
Chiral column is bonded chiral chromatographic column CHIRALPAK IE.
Described organic solvent is the mixture being made up of normal hexane and dehydrated alcohol, and the volume ratio of the two is, just own
Alkane: dehydrated alcohol=80: 20.Described flow rate of mobile phase is 5mL/min, and chromatogram column temperature is 32 DEG C, and detection wavelength is 254
nm.Described sample size is 5mL.Flowing the most by volume percentage calculation, normal hexane: dehydrated alcohol=60: 40.
Embodiment 6, the methods experiment one of a kind of high performance liquid chromatography fractionation canagliflozin five-membered ring impurity enantiomer:
By five-membered ring impurity mixture of enantiomers 1 ~ 2ml chromatographic grade anhydrous alcohol solution, use analytical type high performance liquid chromatography
Instrument carries out isolated and purified, and column size is 0.46 cm I.D. × 15 cm L, and Silica Surface is covalently bonded with straight chain and forms sediment
Powder-three (3,5-Dichlorobenzene base carbamate) filler is Daicel medicine chiral technology (Shanghai) Co., Ltd. product, particle diameter
Being 5 μm, sample introduction 2 μ l, chromatogram column temperature is 35 DEG C, and flowing is normal hexane/dehydrated alcohol (60/40, V/V) mutually, isocratic elution
1ml/min, elution time 8min.The detection wavelength of the New UV Spectrophotometric detector used is 254nm.
Chromatographic isolation result as shown in Figure 1, from Fig. 1 it can be seen that R-configuration five-membered ring impurity chromatographic peak is when retaining
Between be the five-membered ring impurity chromatographic peak retention time of 5.043min, S-configuration be 6.099min, R-configuration and five yuan of S-configuration
Both ring impurity separating degree is 2.637.
Embodiment 7, the methods experiment two of a kind of high performance liquid chromatography fractionation canagliflozin five-membered ring impurity enantiomer:
By five-membered ring impurity mixture of enantiomers 1 ~ 2ml chromatographic grade anhydrous alcohol solution, use analytical type high performance liquid chromatography
Instrument carries out isolated and purified, and column size is 0.46 cm I.D. × 25 cm L, and Silica Surface is covalently bonded with straight chain and forms sediment
Powder-three (3,5-Dichlorobenzene base carbamate) filler is Daicel medicine chiral technology (Shanghai) Co., Ltd. product, particle diameter
Being 5 μm, sample introduction 30 μ l, chromatogram column temperature is 35 DEG C, and flowing is normal hexane/dehydrated alcohol (60/40, V/V) mutually, isocratic elution
1ml/min, elution time 20min.The detection wavelength of the New UV Spectrophotometric detector used is 254nm, R-configuration five-membered ring impurity
Chromatographic peak retention time is 10.864 min, and the five-membered ring impurity chromatographic peak retention time of S-configuration is 11.974min, R-structure
The five-membered ring impurity separating degree of type and S-configuration is 2.391.
Chromatographic isolation result as shown in Figure 2, from figure 2 it can be seen that R-configuration five-membered ring impurity chromatographic peak retention time
Five-membered ring impurity chromatographic peak retention time for 10.864min, S-configuration is 11.974min, R-configuration and five yuan of S-configuration
Both ring impurity separating degree is 2.391.
Embodiment 8, the methods experiment three of a kind of high performance liquid chromatography fractionation canagliflozin five-membered ring impurity enantiomer:
By five-membered ring impurity mixture of enantiomers 10ml chromatographic grade anhydrous alcohol solution, use preparative high performance liquid chromatography instrument
Carrying out isolated and purified, column size is 5.0 cm I.D. × 25 cm L, and Silica Surface is covalently bonded with amylose-three
(3,5-Dichlorobenzene base carbamate) filler is Daicel medicine chiral technology (Shanghai) Co., Ltd. product, applied sample amount
231.9mg, sample introduction 10ml, chromatogram column temperature is 35 DEG C, and flowing is normal hexane/dehydrated alcohol (60/40, V/V) mutually, isocratic elution
60ml/min, elution time 8min.The detection wavelength of New UV Spectrophotometric detector used is 254nm, collect respectively R-configuration and
The five-membered ring impurity of S-configuration.Collection liquid 40 DEG C is concentrated to dryness.
Optical purity testing result is as shown in Fig. 3 ~ 4, from figure 3, it can be seen that R-configuration five-membered ring impurity ee% is
99.90%.Figure 4, it is seen that the five-membered ring impurity ee% of S-configuration is 98.68%.
R-configuration five-membered ring impurity yield: 0.1330g(57.4%), S-configuration five-membered ring impurity yield: 0.0940g
(40.5%), total recovery is 97.9%.
R-configuration five-membered ring impurity HRMS:[M+Na]+= 467.13190；MS:[M+Na]+=467
R-configuration five-membered ring impurity1H-NMR(CDCl3,400M): δ=7.59 (dd, 2H)；7.27 (d, 1H)；7.26 (s, 1H)；
7.21 (d, 1H)；7.19 (t, 2H)；7.11 (d, 1H)；6.79 (d, 1H)；5.35(s,1H)；4.85 (s, 1H)；4.60 (s, 1H)；
4.46 (d, 3H)；4.41 (s, 1H)；4.11 (s, 2H)；4.00 (s, 1H)；3.85 (m, 1H)；3.82 (m, 1H)；3.81 (m,
1H)；3.64 (d, 1H)；3.44 (dd, 1H)；2.26 (s, 3H).
In sum, the high performance liquid chromatography of a kind of canagliflozin five-membered ring impurity enantiomer of the present invention splits, prepares
Method, effectively can well separate the five-membered ring impurity of R-configuration and S-configuration, and reach quickly to prepare.
The above is only the citing of embodiments of the present invention, it is noted that for the ordinary skill of the art
For personnel, on the premise of without departing from the technology of the present invention principle, it is also possible to make some improvement and modification, these improve and become
Type also should be regarded as protection scope of the present invention.
Claims (10)
1. the method that a high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer, it is characterised in that: by raw material five
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 0.1 ~ 25mg/ml；Use high performance liquid chromatograph, form sediment with straight chain
Powder type chiral column is chromatographic column, carries out mutually splitting preparation with the mixed liquor that normal hexane forms with ethanol for flowing.
Method the most according to claim 1, it is characterised in that: described Amylose-type chiral column is bonded chiral
Chromatographic column CHIRALPAK IE；Filler preferably Silica Surface is covalently bonded with amylose-three (3,5-Dichlorobenzene base amino first
Acid esters).
Method the most according to claim 1, it is characterised in that: described organic solvent is selected from dehydrated alcohol, normal hexane, second
The mixed solvent of one or several compositions in alcohol, methanol.
Method the most according to claim 3, it is characterised in that: described organic solvent is by normal hexane and dehydrated alcohol
The mixture of composition, and the volume ratio of the two is, normal hexane: dehydrated alcohol=40 ~ 80: 60 ~ 20.
Method the most according to claim 4, it is characterised in that: normal hexane: dehydrated alcohol=60: 40.
Method the most according to claim 1, it is characterised in that: described flow rate of mobile phase is 1.0 ~ 70mL/min, chromatograph
Column temperature is 25 ~ 40 DEG C, and detection wavelength is 220 ~ 290 nm.
Method the most according to claim 6, it is characterised in that: described chromatogram column temperature is 30 ~ 35 DEG C, and detection wavelength is
220~254 nm。
Method the most according to claim 1, it is characterised in that: described sample size is 2 μ L ~ 10mL.
Method the most according to claim 1, it is characterised in that: flowing the most by volume percentage calculation, normal hexane: anhydrous
Ethanol is 40 ~ 80: 60 ~ 20, preferably normal hexane: dehydrated alcohol=60: 40.
Method the most according to claim 1, it is characterised in that: raw material five-membered ring impurity mixture of enantiomers is dissolved in organic
Solvent is to concentration 5 ~ 20mg/ml.
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Cited By (4)
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| CN109374783A (en) * | 2018-12-21 | 2019-02-22 | 安徽联创生物医药股份有限公司 | A method of with the related substance of HPLC separation determination canagliflozin bulk pharmaceutical chemicals |
| CN109528710A (en) * | 2018-12-19 | 2019-03-29 | 黄泳华 | Composition containing tolylthiophene class compound |
| CN111077234A (en) * | 2018-10-19 | 2020-04-28 | 重庆医药工业研究院有限责任公司 | Method for separating and determining canagliflozin and impurities thereof by using liquid chromatography |
| CN111514612A (en) * | 2020-04-29 | 2020-08-11 | 江苏德源药业股份有限公司 | Method for rapidly splitting pioglitazone hydrochloride racemate by supercritical fluid chromatography |
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| CN111077234A (en) * | 2018-10-19 | 2020-04-28 | 重庆医药工业研究院有限责任公司 | Method for separating and determining canagliflozin and impurities thereof by using liquid chromatography |
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| CN109374783A (en) * | 2018-12-21 | 2019-02-22 | 安徽联创生物医药股份有限公司 | A method of with the related substance of HPLC separation determination canagliflozin bulk pharmaceutical chemicals |
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| CN111514612A (en) * | 2020-04-29 | 2020-08-11 | 江苏德源药业股份有限公司 | Method for rapidly splitting pioglitazone hydrochloride racemate by supercritical fluid chromatography |
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