CN107796904A - A kind of method with HPLC separation determination o-chloromandelic acid enantiomters - Google Patents
A kind of method with HPLC separation determination o-chloromandelic acid enantiomters Download PDFInfo
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- CN107796904A CN107796904A CN201610782848.3A CN201610782848A CN107796904A CN 107796904 A CN107796904 A CN 107796904A CN 201610782848 A CN201610782848 A CN 201610782848A CN 107796904 A CN107796904 A CN 107796904A
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- 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
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Abstract
This application discloses a kind of method with HPLC separation determination o-chloromandelic acid enantiomters, including, R o-chloromandelic acids sample is subjected to separation determination with HPLC methods, using chiral chromatographic column of 4 methyl benzoic acid esters of the cellulose iii _ chiral chromatographic column as stationary phase during separation determination, and isocratic elution is carried out as mobile phase using the mixed solution of alkane and lower alcohol.This method can simply, quickly and accurately separate the enantiomter impurity of o-chloromandelic acid.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and HPLC separation determination o-chloromandelic acid mappings are used more particularly, to one kind
The method of isomers.
Background technology
The structural formula of o-chloromandelic acid, entitled 2- (2- the chlorphenyls) -2- hydroxyacetic acids of chemistry, its R type and S types is as follows：
There is handedness property in nature life entity, thereby produce the chiral problem of medicine.Pharmaceutical research shows exist
The medicine of chiral enantiomer often only has a kind of enantiomer to have required drug effect, and another kind can not then reach desired drug effect
Effect.Therefore, sustainable growth is needed to single enantiomer medicine in global range.In platelet aggregation-against new drug clopidogrel
In the preparation process of (being clinically widely used in preventing the cardiovascular and cerebrovascular diseases such as miocardial infarction, apoplexy, artery sclerosis), need to have
There are optically active R- o-chloromandelic acids as intermediate.Because the production of clopidogrel is carried out using R- o-chloromandelic acids as raw material
The clopidogrel of single configuration can be obtained, without being split again.Therefore, preparing has optically active R- neighbour's chlorine almond
Acid tool has very important significance.
During R- o-chloromandelic acids are prepared, because o-chloromandelic acid has a chiral centre, therefore always not
The evitable enantiomter for being mixed with o-chloromandelic acid.In order to control the quality of medicine, it is necessary to control pair of o-chloromandelic acid
Reflect the content of isomers.Therefore, the analysis method for establishing reliable separation determination o-chloromandelic acid enantiomter is that have very much
It is necessary.
The content of the invention
, should it is an object of the present invention to provide a kind of method with HPLC separation determination o-chloromandelic acid enantiomters
Method can simply, quickly and accurately separate the enantiomter impurity of o-chloromandelic acid.
To achieve these goals, the present invention adopts the following technical scheme that：
A kind of method with HPLC separation determination o-chloromandelic acid enantiomters, methods described includes, and R- neighbour's chlorine is flat
Peach acid sample carries out separation determination with HPLC methods, using -4- the methyl benzoic acid esters of cellulose-three as chiral color during separation determination
The stationary phase of post is composed, and isocratic elution is carried out as mobile phase using the mixed solution of alkane and lower alcohol.
Preferably, described alkane includes n-hexane, one kind of normal heptane or its mixed liquor；Described lower alcohol includes
One or more kinds of combinations in methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol or isobutanol.
Preferably, in the mobile phase, the volume ratio of alkane and lower alcohol is 980：20~550：450；It is preferred that the stream
In dynamic phase, the volume ratio of alkane and lower alcohol is 900:100~600:400.
Preferably, before carrying out separation determination with HPLC methods, acid flux material is added in described mobile phase, wherein acid molten
The volume of agent accounts for the 0.03~4.0% of mobile phase cumulative volume.
Preferably, described acid flux material includes one or more kinds of combinations in formic acid, acetic acid or trifluoroacetic acid.
Preferably, when carrying out HPLC detections, column temperature is 10 DEG C~40 DEG C, sample size 5-15uL, Detection wavelength 200
~250nm；The flow velocity of mobile phase is 0.3~2.5ml/min.
Preferably, when carrying out HPLC detections, using the mixed solution of n-hexane, ethanol, methanol and trifluoroacetic acid as stream
Dynamic phase, in the mixed solution, n-hexane, ethanol, methanol, trifluoroacetic acid volume ratio are 900：80：20：1；Using ultraviolet detection
Device, Detection wavelength are 230nm；The flow velocity of mobile phase is 1.5ml/min；Column temperature is 16 DEG C.
Preferably, before HPLC detections are carried out, in addition to the mistake that the R- o-chloromandelic acids crude product is dissolved with isopropanol
Journey.
Preferably, after R- o-chloromandelic acids crude product is dissolved with isopropanol, in addition to with the consistent solution of flowing phase constituent
It is diluted and is configured to the process of 0.2~5.0mg/mL o-chloromandelic acid solution.
Preferably, described R- o-chloromandelic acid samples refer to the mixing comprising R- o-chloromandelic acids and S- o-chloromandelic acids
Thing.
Beneficial effect caused by the application energy includes but is not limited to：
1) the chiral chromatographic column of -4- methyl benzoic acid esters of cellulose-three provided herein as chiral stationary phase, can
To efficiently separate the enantiomter of o-chloromandelic acid.Chiral chromatographic column (Chiral HPLC Columns) is by with light
The monomer of activity is learned, is fixed on silica gel or other polymer and chiral stationary phase (Chiral Stationary is made
Phases).Separation for chiral isomer, the isomers of different chemical property need to use different types of chiral column how
It is very important according to the chiral chromatographic column that the selection of the molecular structure of compound is applicable.The selectable chiral chromatographic column of in the market
It is more and more, according to the chemical constitution of stationary phase, chiral chromatographic column is divided into following several：Brush-type, glycan, cyclodextrin type,
Macrocyclic antibiotic type, protein type, ligand exchange type, crown ether type etc..Inventor once attempts to select separating chiral compound more normal
Multiple chiral chromatographic columns of cyclodextrin type carry out the separation determination of o-chloromandelic acid and its chiral isomer, but no matter such as
What adjustment mobile phase and other chromatographic conditions can not all separate each peak, and the signal of chromatographic peak is weaker and peak shape is poor.Inventor couple
Polysaccharide derivates type chromatographic column is investigated, and the chromatographic column of wherein stationary phase Silica Surface coated fiber element derivative can be realized
Separation.By long-term experiment, finally found that using Silica Surface coated cellulose-tri- (4-methyl benzoic acid ester) as solid
Determine the chiral chromatographic column of phase, and eluted using appropriate organic solvent, the mapping of o-chloromandelic acid can be efficiently separated
Isomers.
Above-mentioned chromatographic column is the chiral chromatogram that stationary phase is plain-tri- (the 4 monomethyl benzoic ethers) of Silica Surface coated fiber
Post, it is the chiral column of Japanese Daicel company production.Such chiral chromatographic column can reach preferable separating effect, for it
Fractionation mechanism, it is considered that there is dipole-dipole between enantiomer and stationarity, hydrogen bond-hydrogen bond, π-π, size exclusion,
A variety of interactions such as hydrophobic inclusion, due to these solid effects and the presence of electrical function so that two enantiomers and fixation
Property the stability of diastereomer complex compound that is formed create a difference so as to realize separation.
It is 2) provided herein that isocratic elution is carried out as mobile phase using the mixed solution of alkane and lower alcohol so that
Its separating degree is higher.Investigate and find by experiment, the ratio of alkane and lower alcohol in the separating degree and mobile phase of two enantiomers
And the species of organic additive is relevant with addition.Found simultaneously when investigating influence of the column temperature to separating degree, positive is washed
Column temperature is reduced in de- system to be advantageous to improve separating degree, R- o-chloromandelic acids is more completely separated with S- o-chloromandelic acids.
3) a kind of method with HPLC separation determination o-chloromandelic acid enantiomters provided herein, with existing skill
The method with HPLC separation determination o-chloromandelic acid enantiomters in art is compared, and sample itself need not be done first any
Derivatization treatment, mobile phase are also the solvent of common normal-phase chromatography, it is not necessary to any Chiral Mobile Phase Additives.Therefore, originally
The there is provided method of application is simple compared with the method for prior art.Moreover, method interference factor provided herein is few, determining
During blank be not present disturb, and high sensitivity, R is more than 1.7 for its separating degree.
Brief description of the drawings
Fig. 1：Blank solution chromatogram in embodiment 1；
Fig. 2：System suitability solution chromatogram in embodiment 1；
Fig. 3：The Plays product solution chromatogram of embodiment 1；
Fig. 4：Need testing solution chromatogram in embodiment 1.
Embodiment
The application is described in detail with reference to embodiment, but the application is not limited to these embodiments.
Reagent used in the present invention can from the market be bought or can be by method system described in the invention
It is standby and obtain.
Analytical reagent and solution used in the present invention meet the requirement of 2015 editions annex of Chinese Pharmacopoeia, unless otherwise indicated
Outside.
Heretofore described separating degree R refers to the ratio of the difference and average peak width of the retention time at adjacent two peak.Also referred to as
Resolution ratio, represent the separation degree at adjacent two peak.R is bigger, shows that two adjacent groups point separation is better.Generally as R ＜ 1, two
Peak overlaps；As R=1.0, separating degree is up to 98%；As R=1.5, separating degree is up to 99.7%.Generally use R=
1.5 marks being kept completely separate as two adjacent groups point.As R=1, referred to as 4 σ separation, two peaks are basically separated, exposed peak area
For 95.4%, inner side peak base overlapping about 2%.During R=1.5, referred to as 6 σ separation, exposed peak area is 99.7%.R >=1.5 are referred to as
It is kept completely separate.《Chinese Pharmacopoeia》Regulation R should be greater than 1.5.
Separating degree calculation formula：R=2 (tR2-tR1)/(W1+W2)
tR2:The retention time at latter peak in adjacent two peak；
tR1:The retention time at previous peak in adjacent two peak；
W1、W2:The peak width at this adjacent two peak
Embodiment 1
A kind of method with HPLC separation determination o-chloromandelic acid enantiomters, comprise the following steps：
(1) for the preparation of detection solution：
The preparation of system suitability solution：Take o-chloromandelic acid raceme reference substance about 10mg, it is accurately weighed to hold to 25mL
Measuring bottle, dissolved with diluent and be diluted to scale, shaken up, as system suitability solution.
The preparation of standard solution：Take R- o-chloromandelic acids standard items about 10mg, in the accurately weighed volumetric flask to 25mL, use
Diluent ultrasonic dissolution is simultaneously diluted to scale, shakes up, as standard solution.
The preparation of need testing solution：Being derived from R- o-chloromandelic acids processed, (specific preparation method is with reference to patent《It is prepared by a kind of enzyme process
The method of R- o-chloromandelic acids and application》, application number：201510978973.7) appropriate sample, about 10mg, put 25ml volumetric flasks
In, add a small amount of isopropanol to dissolve and be diluted to scale with the solution consistent with mobile phase solution, shake up, filter, filtrate is as confession
Test sample solution.
(2) HPLC detections separation
Chromatographic condition：Wear peace U3000 types highly effective liquid phase chromatographic system and work station；
Chromatographic column：OJ-H, 4.6 × 250mm, 5um；
Detector：UV-detector, Detection wavelength are about 230nm；
The flow velocity of mobile phase is 1.5ml/min；Sampling volume：10uL；
Run time：40min；Remaining condition is see table 1
According to second annex VD high performance liquid chromatography of Chinese Pharmacopoeia 2015 edition, take blank solution, system suitability molten
Liquid and need testing solution, and standard solution, the sample detection under the chromatographic condition, and chromatogram is recorded, the knot of experiment
Fruit sees Fig. 1, Fig. 2, Fig. 3 and Fig. 4.
Table 1
By embodiment, the method for the enantiomter provided by the invention with HPLC separation determination o-chloromandelic acids,
Blank is not present in continuous mode to disturb, and high sensitivity, R is more than 1.7 for its separating degree, complies fully with《Chinese Pharmacopoeia》Regulation
R should be greater than 1.5 regulation.
Comparative example 1
As described in Example 1, different parts is see table 2 for remaining step and condition.
Table 2
As can be seen from the above table, under conditions of comparative example provides, its separating resulting is undesirable, and separating degree is not met
《Chinese Pharmacopoeia》Regulation R should be greater than 1.5 regulation.
Comparative example 2
According to《Analytical chemistry》In July, 2005, Wang Jin was towards, " the high performance liquid chromatography Chiral mobile phase additives point once revived
From mandelic acid and o-chloromandelic acid enantiomer " it is prepared by the method provided in article, and its separating degree R is 1.12, is not met
《Chinese Pharmacopoeia》Regulation R should be greater than 1.5 regulation.And due to adding Chiral Mobile Phase Additives, not only method is complicated, and
And interference factor is more.According to《5th national pharmaceutical engineering science and technology can collection of thesis with Teaching research》On November 24th, 2006 Xu Xu
Prepared Deng the method provided in " derivatization HPLC methods split mandelic acid enantiomer " article, its separating degree R 1.58 with
On.However, this method need first with aniline, alpha naphthylamine is by chiral thing mandelic acid derivatization, then carry out HPLC detections.
In summary, this application provides a kind of method with HPLC separation determination o-chloromandelic acid enantiomters, side
Method is simple and reliable, and interference factor is few, and separating degree is high.
It is described above, only it is several embodiments of the application, any type of limitation is not done to the application, although this Shen
Please with preferred embodiment disclose as above, but and be not used to limit the application, any person skilled in the art, do not taking off
In the range of technical scheme, make a little variation using the technology contents of the disclosure above or modification is equal to
Case study on implementation is imitated, is belonged in the range of technical scheme.
Claims (10)
- A kind of 1. method with HPLC separation determination o-chloromandelic acid enantiomters, it is characterised in that methods described includes, will R- o-chloromandelic acids sample carries out separation determination with HPLC methods, is made using -4- the methyl benzoic acid esters of cellulose-three during separation determination For the stationary phase of chiral chromatographic column, and using the mixed solution of alkane and lower alcohol as mobile phase progress isocratic elution.
- 2. according to the method for claim 1, it is characterised in that described alkane include n-hexane, normal heptane one kind or Its mixed liquor of person；Described lower alcohol includes one kind or one in methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol or isobutanol The combination of the kind above.
- 3. according to the method described in claim 1 or 2, it is characterised in that in the mobile phase, the volume of alkane and lower alcohol Than for 980：20~550：450；It is preferred that in the mobile phase, the volume ratio of alkane and lower alcohol is 900：100~600: 400.
- 4. according to the method described in any one in claim 1-3, it is characterised in that before carrying out separation determination with HPLC methods, Acid flux material is added in described mobile phase, the volume of wherein acid flux material accounts for the 0.03~4.0% of mobile phase cumulative volume.
- 5. according to the method described in any one in claim 1-4, it is characterised in that described acid flux material include formic acid, One or more kinds of combinations in acetic acid or trifluoroacetic acid.
- 6. according to the method described in any one in claim 1-5, it is characterised in that when carrying out HPLC detections, column temperature is 10 DEG C~40 DEG C, sample size 5-15uL, Detection wavelength is 200~250nm；The flow velocity of mobile phase is 0.3~2.5mL/min.
- 7. according to the method described in any one in claim 1-6, it is characterised in that when carrying out HPLC detections, will just oneself Alkane, ethanol, the mixed solution of methanol and trifluoroacetic acid are as mobile phase, in the mixed solution, n-hexane, ethanol, methanol, three Fluoroacetic acid volume ratio is 900: 80: 20：1；Using UV-detector, Detection wavelength is 230nm；The flow velocity of mobile phase is 1.5mL/ min；Column temperature is 16 DEG C.
- 8. according to the method described in any one in claim 1-7, it is characterised in that before HPLC detections are carried out, in addition to The process that the R- o-chloromandelic acids crude product is dissolved with isopropanol.
- 9. according to the method described in any one in claim 1-8, it is characterised in that R- o-chloromandelic acid crude product isopropanols After dissolving, in addition to it is diluted with the solution consistent with flowing phase constituent and is configured to 0.2~5.0mg/mL o-chloromandelic acids The process of solution.
- 10. according to the method described in any one in claim 1-9, it is characterised in that described R- o-chloromandelic acid samples Refer to the mixture comprising R- o-chloromandelic acids and S- o-chloromandelic acids.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109529794A (en) * | 2018-12-27 | 2019-03-29 | 中国人民解放军第四军医大学 | Optical pure mandel derivative-Cellulose chiral stationaryphase, preparation method and application |
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| EP1382674A2 (en) * | 2002-07-16 | 2004-01-21 | Daicel Chemical Industries, Ltd. | Alpha-keto acid reductase, method for producing the same, and method for producing optically active alpha-hydroxy acids using the same |
| WO2007126258A1 (en) * | 2006-04-27 | 2007-11-08 | Enzytech, Ltd | The method of making optically active 2-halo-2-(n-substituted phenyl)acetic acid esters and 2-halo-2-(n-substituted phenyl)acetic acids by enzymatic method |
| CN102260657A (en) * | 2011-07-15 | 2011-11-30 | 华东理工大学 | Lipase gene and recombinase thereof, and application of lipase gene in preparing optically active mandelic acid |
| CN102533705A (en) * | 2012-02-24 | 2012-07-04 | 华东理工大学 | Nitrilase and gene and application thereof |
| CN105349583A (en) * | 2015-12-23 | 2016-02-24 | 武汉武药制药有限公司 | Method for preparing (R)-o-chloromandelic acid through enzyme and application of enzyme |
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2016
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1382674A2 (en) * | 2002-07-16 | 2004-01-21 | Daicel Chemical Industries, Ltd. | Alpha-keto acid reductase, method for producing the same, and method for producing optically active alpha-hydroxy acids using the same |
| WO2007126258A1 (en) * | 2006-04-27 | 2007-11-08 | Enzytech, Ltd | The method of making optically active 2-halo-2-(n-substituted phenyl)acetic acid esters and 2-halo-2-(n-substituted phenyl)acetic acids by enzymatic method |
| CN102260657A (en) * | 2011-07-15 | 2011-11-30 | 华东理工大学 | Lipase gene and recombinase thereof, and application of lipase gene in preparing optically active mandelic acid |
| CN102533705A (en) * | 2012-02-24 | 2012-07-04 | 华东理工大学 | Nitrilase and gene and application thereof |
| CN105349583A (en) * | 2015-12-23 | 2016-02-24 | 武汉武药制药有限公司 | Method for preparing (R)-o-chloromandelic acid through enzyme and application of enzyme |
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| 王敏: "Chiralpak AD-H和Chiralcel OJ-H手性固定相拆分扁桃酸系列化合物", 《色谱》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109529794A (en) * | 2018-12-27 | 2019-03-29 | 中国人民解放军第四军医大学 | Optical pure mandel derivative-Cellulose chiral stationaryphase, preparation method and application |
| CN109529794B (en) * | 2018-12-27 | 2021-12-17 | 中国人民解放军第四军医大学 | Optical pure mandelic acid derivative-cellulose chiral stationary phase, preparation method and application |
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