CN106226426B - A kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer - Google Patents
A kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer Download PDFInfo
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- CN106226426B CN106226426B CN201610564044.6A CN201610564044A CN106226426B CN 106226426 B CN106226426 B CN 106226426B CN 201610564044 A CN201610564044 A CN 201610564044A CN 106226426 B CN106226426 B CN 106226426B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention discloses a kind of methods 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 0.1 ~ 25mg/ml of concentration；Using high performance liquid chromatograph, using Amylose-type chiral column as chromatographic column, fractionation preparation is carried out by mobile phase of the mixed liquor that n-hexane and ethyl alcohol form.The present invention splits the high income of preparation canagliflozin five-membered ring impurity enantiomer, and purity can reach 98% or more, is suitable as the use of new drug development reference substance.This method effectively realizes the separation and preparation of R, S configuration in five-membered ring impurity enantiomer, and separating degree is up to 2.6 or more.High performance liquid chromatography splits high degree of automation, and preparation efficiency is high.
Description
Technical field
The present invention relates to a kind of fractionation technology of chiral impurity in drug, especially a kind of high performance liquid chromatography splits card lattice
The method for arranging net five-membered ring impurity enantiomer belongs to pharmaceutical technology field.
Background technique
Canagliflozin (Canagliflozin) is the first SGLT2 inhibitor of FDA approval, for treating adult patients
Type-2 diabetes mellitus, be a kind of new white 2(SGLT2 of sodium glucose co-transporter 2) inhibitor medicaments, pass through and inhibit kidney pair
The reabsorption of glucose increases glucose excretion, and then reduces the elevated blood glucose level of diabetic.
Due to must be strictly controlled by-product R, S- the configuration five-membered ring impurity that its synthesis process generates in canagliflozin
Content, R, S- configuration five-membered ring mixtures of impurities are difficult to separate using conventional method, and structure elucidation and accurate can not be carried out to it
Quantitative study, because of a kind of R of the invention, the liquid chromatogram method for splitting of S- configuration five-membered ring impurity is particularly important.
R, S- configuration five-membered ring impurity structural formula are as follows:
。
Summary of the invention
The object of the present invention is to provide a kind of methods that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer.
The present invention is for achieving the above object the technical solution adopted is as follows: a kind of high performance liquid chromatography splits Ka Gelie
The method of net five-membered ring impurity enantiomer, its main feature is that: raw material five-membered ring impurity mixture of enantiomers is dissolved in organic solvent extremely
0.1 ~ 25mg/ml of concentration；Using high performance liquid chromatograph, using Amylose-type chiral column as chromatographic column, with n-hexane and ethyl alcohol
The mixed liquor of composition is that mobile phase carries out fractionation preparation.
The method that institute's art guest's high performance liquid chromatography of the present invention splits canagliflozin five-membered ring impurity enantiomer: the straight chain
Starch type chiral column is preferably bonded chiral chromatographic column CHIRALPAK IE；Filler is preferably that Silica Surface is covalently bonded with directly
Chain starch-three (3,5- dichlorophenyl carbamate).
One of the preferred dehydrated alcohol of organic solvent described in the method for the present invention, n-hexane, ethyl alcohol, methanol are several
The mixed solvent of kind composition.The mixture being particularly preferably made of n-hexane and dehydrated alcohol, and the volume ratio of the two is, just
Hexane: dehydrated alcohol=40 ~ 80: 60 ~ 20, further preferred n-hexane: dehydrated alcohol=60: 40.
In the method for the present invention, the 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.The chromatogram column temperature is more preferably 30 ~ 35 DEG C, and Detection wavelength is further
Preferably 220 ~ 254 nm.The sample volume is preferably 2 μ L ~ 10mL.
Mobile phase of the present invention is calculated by percent by volume, preferably n-hexane: dehydrated alcohol is 40 ~ 80: 60 ~
20, most preferably n-hexane: dehydrated alcohol=60: 40.
In the method for the present invention, 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, it is miscellaneous to have following technical effect that the present invention splits preparation canagliflozin five-membered ring by the present invention
The high income of matter enantiomer, purity can reach 98% or more, be suitable as the use of new drug development reference substance.The method of the present invention is effective
The separation and preparation for realizing R configuration, S configuration in five-membered ring impurity enantiomer, separating degree is up to 2.6 or more.Efficient liquid
Phase Chromatographic resolution high degree of automation, preparation efficiency are high.
Detailed description of the invention
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.
Specific embodiment
The present invention is further described below by specific embodiment and in conjunction with attached drawing, but is not intended to limit the present invention.
Embodiment 1, a kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer: by five yuan of raw material
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 0.1mg/ml；Using high performance liquid chromatograph, with Amylose-type
Chiral column is chromatographic column, carries out fractionation preparation by mobile phase of the mixed liquor that n-hexane and ethyl alcohol form.The amylose
Type chiral column is bonded chiral chromatographic column CHIRALPAK IE.The organic solvent is selected from dehydrated alcohol, n-hexane, second
One of alcohol, methanol；The flow rate of mobile phase is 1.0mL/min, and chromatogram column temperature is 25 DEG C, Detection wavelength 220nm.
The sample volume is 2 μ L.Mobile phase is calculated by percent by volume, n-hexane: dehydrated alcohol 40:60.
Embodiment 2, a kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer: by five yuan of raw material
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 25mg/ml；Using high performance liquid chromatograph, with Amylose-type hand
Property column be chromatographic column, carry out fractionation preparation by mobile phase of the mixed liquor that n-hexane and ethyl alcohol form.The Amylose-type
Chiral column is bonded chiral chromatographic column CHIRALPAK IE.Filler is preferably that Silica Surface is covalently bonded with amylose-three
(3,5- dichlorophenyl carbamate).
The mixed solvent of two kind composition of the organic solvent in dehydrated alcohol, n-hexane, ethyl alcohol, 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.The sample volume is
10mL.Mobile phase is calculated by percent by volume, n-hexane: dehydrated alcohol 80: 20,
Embodiment 3, a kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer: by five yuan of raw material
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 5mg/ml；Using high performance liquid chromatograph, with Amylose-type hand
Property column be chromatographic column, carry out fractionation preparation by mobile phase of the mixed liquor that n-hexane and ethyl alcohol form.The Amylose-type
Chiral column is bonded chiral chromatographic column CHIRALPAK IE.
The mixed solvent of three kind composition of the organic solvent in dehydrated alcohol, n-hexane, ethyl alcohol, methanol.
The flow rate of mobile phase is 10mL/min, and chromatogram column temperature is 30 DEG C, and Detection wavelength is 280 nm.It is described into
Sample amount is 1mL.Mobile phase is calculated by percent by volume, n-hexane: dehydrated alcohol 50: 50.
Embodiment 4, a kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer: by five yuan of raw material
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 20mg/ml；Using high performance liquid chromatograph, with Amylose-type hand
Property column be chromatographic column, carry out fractionation preparation by mobile phase of the mixed liquor that n-hexane and ethyl alcohol form.The Amylose-type
Chiral column is bonded chiral chromatographic column CHIRALPAK IE.
The organic solvent is the mixture being made of n-hexane and dehydrated alcohol, and the volume ratio of the two is, just oneself
Alkane: dehydrated alcohol=60: 40.The flow rate of mobile phase is 30mL/min, and chromatogram column temperature is 35 DEG C, and Detection wavelength is
254nm.The sample volume is 5mL.Mobile phase is calculated by percent by volume, n-hexane: dehydrated alcohol=60: 40.
Embodiment 5, a kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer: by five yuan of raw material
Ring impurity mixture of enantiomers is dissolved in organic solvent to concentration 1mg/ml；Using high performance liquid chromatograph, with Amylose-type hand
Property column be chromatographic column, carry out fractionation preparation by mobile phase of the mixed liquor that n-hexane and ethyl alcohol form.The Amylose-type
Chiral column is bonded chiral chromatographic column CHIRALPAK IE.
The organic solvent is the mixture being made of n-hexane and dehydrated alcohol, and the volume ratio of the two is, just oneself
Alkane: dehydrated alcohol=80: 20.The flow rate of mobile phase is 5mL/min, and chromatogram column temperature is 32 DEG C, Detection wavelength 254
nm.The sample volume is 5mL.Mobile phase is calculated by percent by volume, n-hexane: dehydrated alcohol=60: 40.
Embodiment 6, a kind of high performance liquid chromatography split the methods experiment one of canagliflozin five-membered ring impurity enantiomer:
Five-membered ring impurity mixture of enantiomers 1 ~ 2ml chromatographic grade dehydrated alcohol is dissolved, using analytic type efficient liquid phase
Chromatograph is isolated and purified, and column size is the 0.46 cm L of cm I.D. × 15, and Silica Surface is covalently bonded with straight chain
(3, the 5- dichlorophenyl carbamate) filler of starch-three is Daicel drug chiral technology (Shanghai) Co., Ltd. product, grain
Diameter is 5 μm, 2 μ l of sample introduction, and chromatogram column temperature is 35 DEG C, and mobile phase is n-hexane/dehydrated alcohol (60/40, V/V), isocratic elution
1ml/min, elution time 8min.The Detection wavelength of the New UV Spectrophotometric detector used is 254nm.
Shown in chromatographic isolation the result is shown in Figure 1, from Fig. 1 as can be seen that when R-configuration five-membered ring impurity chromatographic peak retains
Between be 5.043min, the five-membered ring impurity chromatographic peak retention time of S- configuration is 6.099min, five yuan of R-configuration and S- configuration
Both ring impurity separating degree is 2.637.
Embodiment 7, a kind of high performance liquid chromatography split the methods experiment two of canagliflozin five-membered ring impurity enantiomer:
Five-membered ring impurity mixture of enantiomers 1 ~ 2ml chromatographic grade dehydrated alcohol is dissolved, using analytic type efficient liquid phase
Chromatograph is isolated and purified, and column size is the 0.46 cm L of cm I.D. × 25, and Silica Surface is covalently bonded with straight chain
(3, the 5- dichlorophenyl carbamate) filler of starch-three is Daicel drug chiral technology (Shanghai) Co., Ltd. product, grain
Diameter is 5 μm, 30 μ l of sample introduction, and chromatogram column temperature is 35 DEG C, and mobile phase is n-hexane/dehydrated alcohol (60/40, V/V), 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
Both the five-membered ring impurity of type and S- configuration separating degree 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
For 10.864min, the five-membered ring impurity chromatographic peak retention time of S- configuration is 11.974min, five yuan of R-configuration and S- configuration
Both ring impurity separating degree is 2.391.
Embodiment 8, a kind of high performance liquid chromatography split the methods experiment three of canagliflozin five-membered ring impurity enantiomer:
Five-membered ring impurity mixture of enantiomers 10ml chromatographic grade dehydrated alcohol is dissolved, using preparative high-efficient liquid phase color
Spectrometer is isolated and purified, and column size is the 5.0 cm L of cm I.D. × 25, and Silica Surface is covalently bonded with straight chain shallow lake
(3, the 5- dichlorophenyl carbamate) filler of powder-three is Daicel drug chiral technology (Shanghai) Co., Ltd. product, loading
231.9mg, sample introduction 10ml are measured, chromatogram column temperature is 35 DEG C, and mobile phase is n-hexane/dehydrated alcohol (60/40, V/V), isocratic to wash
De- 60ml/min, elution time 8min.The Detection wavelength of the New UV Spectrophotometric detector used collects R-configuration for 254nm respectively
With the five-membered ring impurity of S- configuration.40 DEG C of collection liquid are 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 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 conclusion a kind of high performance liquid chromatography of canagliflozin five-membered ring impurity enantiomer of the invention splits, prepares
The five-membered ring impurity of R- configuration and S- configuration can be separated effectively well, and reach quick preparation by method.
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, without departing from the technical principles of the invention, several improvements and modifications can also be made, these improve and become
Type also should be regarded as protection scope of the present invention.
Claims (9)
1. a kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer, it is characterised in that: by raw material five
Member ring impurity mixture of enantiomers is dissolved in organic solvent to 0.1 ~ 25mg/ml of concentration；Using high performance liquid chromatograph, formed sediment with straight chain
Powder type chiral column is chromatographic column, carries out fractionation preparation by mobile phase of the mixed liquor that n-hexane and dehydrated alcohol form；
The flow rate of mobile phase is 1.0 ~ 70mL/min, and chromatogram column temperature is 25 ~ 40 DEG C, and Detection wavelength is 220 ~ 290 nm；
Mobile phase is calculated by percent by volume, n-hexane: dehydrated alcohol is 40 ~ 80: 60 ~ 20.
2. according to the method described in claim 1, it is characterized by: the Amylose-type chiral column is bonded chiral color
Compose column CHIRALPAK IE；Filler is that Silica Surface is covalently bonded with amylose-three (3,5- dichlorophenyl carbamate).
3. according to the method described in claim 1, it is characterized by: the organic solvent is selected from dehydrated alcohol, n-hexane, second
The mixed solvent of one of alcohol, methanol or several compositions.
4. according to the method described in claim 3, it is characterized by: the organic solvent is by n-hexane and dehydrated alcohol group
At mixture, and the volume ratio of the two is n-hexane: dehydrated alcohol=40 ~ 80: 60 ~ 20.
5. according to the method described in claim 4, it is characterized by: in organic solvent, n-hexane: dehydrated alcohol=60: 40.
6. according to the method described in claim 1, Detection wavelength is it is characterized by: the chromatogram column temperature is 30 ~ 35 DEG C
220~254 nm。
7. according to the method described in claim 1, it is characterized by: sample volume is 2 μ L ~ 10mL.
8. according to the method described in claim 1, it is characterized by: mobile phase is by percent by volume calculating, n-hexane: anhydrous second
Alcohol=60: 40.
9. according to the method described in claim 1, it is characterized by: raw material five-membered ring impurity mixture of enantiomers be dissolved in it is organic molten
Agent is to 5 ~ 20mg/ml of concentration.
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| CN111077234B (en) * | 2018-10-19 | 2023-09-15 | 重庆医药工业研究院有限责任公司 | Method for separating and measuring canagliflozin and impurities thereof by liquid chromatography |
| CN109528710A (en) * | 2018-12-19 | 2019-03-29 | 黄泳华 | Composition containing tolylthiophene class compound |
| CN109374783B (en) * | 2018-12-21 | 2022-02-01 | 安徽联创生物医药股份有限公司 | Method for separating and determining related substances of canagliflozin bulk drug by using HPLC (high performance liquid chromatography) |
| CN111514612B (en) * | 2020-04-29 | 2022-04-26 | 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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