CN114544810A - HPLC detection method for chiral purity of paluvird starting material and enantiomer thereof - Google Patents
HPLC detection method for chiral purity of paluvird starting material and enantiomer thereof Download PDFInfo
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- CN114544810A CN114544810A CN202210142617.1A CN202210142617A CN114544810A CN 114544810 A CN114544810 A CN 114544810A CN 202210142617 A CN202210142617 A CN 202210142617A CN 114544810 A CN114544810 A CN 114544810A
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- starting material
- enantiomer
- chiral purity
- paroxetine
- chiral
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- 239000007858 starting material Substances 0.000 title claims abstract description 46
- 238000001514 detection method Methods 0.000 title claims abstract description 20
- 238000004128 high performance liquid chromatography Methods 0.000 title claims abstract description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012488 sample solution Substances 0.000 claims abstract description 16
- 238000000926 separation method Methods 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 238000010829 isocratic elution Methods 0.000 claims abstract description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000004676 glycans Chemical class 0.000 claims abstract description 4
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 4
- 239000005017 polysaccharide Substances 0.000 claims abstract description 4
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 10
- 238000010828 elution Methods 0.000 claims description 9
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 8
- 229960002296 paroxetine Drugs 0.000 claims description 8
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000005526 G1 to G0 transition Effects 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007983 Tris buffer Substances 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 239000011248 coating agent Substances 0.000 abstract description 3
- 238000000576 coating method Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000000523 sample Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000010408 sweeping Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- PXVJVLUFXJFADP-UHFFFAOYSA-N 2-methylhexanoic acid;hydrochloride Chemical compound Cl.CCCCC(C)C(O)=O PXVJVLUFXJFADP-UHFFFAOYSA-N 0.000 description 1
- 208000025721 COVID-19 Diseases 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960005183 paroxetine hydrochloride Drugs 0.000 description 1
Images
Classifications
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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
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N30/54—Temperature
Abstract
The invention discloses a HPLC detection method of chiral purity of a paluwei de starting material and an enantiomer thereof, which comprises the steps of dissolving the paluwei de starting material with isopropanol to prepare a sample solution, injecting 5 mu L of the sample solution into a liquid chromatograph to complete separation of the paluwei de starting material and the enantiomer thereof, and detecting the ee% value of the chiral purity; the method adopts a coating type polysaccharide derivative chiral column and a normal-phase n-hexane/isopropanol chromatographic system to carry out isocratic elution separation, can rapidly separate the starting materials of the palovir and the enantiomers thereof, and ensures the accurate reliability of the ee% value of the chemical purity of the palovir starting materials.
Description
Technical Field
The invention belongs to a High Performance Liquid Chromatography (HPLC) method, and particularly relates to a method for detecting separation of a paluwed starting material and an enantiomer thereof by using HPLC.
Background
Parovirid is used clinically for treating novel coronavirus pneumonia (COVID-19)A starting material in the preparation process of the compound has the structural formula
The molecular formula is C9H15NO2HCl, chemical name Methyl (1R,2S,5S) -6,6-dimethyl-3-azabicyclo [3.1.0]The molecule of the hexane-2-carboxylate-hydrochloride contains three chiral carbon atoms, and the content of the starting material and the enantiomer thereof needs to be controlled in the process of synthesizing the target compound of the paroxetine hydrochloride through orientation.
The synthesis of the starting material is a very key step in the process of directionally synthesizing the target compound, namely the paluvirde, and the chiral purity of the starting material is an important index for controlling the quality of the starting material, so that the separation of the starting material and the enantiomer thereof is of great significance to the quality control in the synthesis process of the paluvirde medicament.
Until now, methods for separating the isomers have been available on the market, but in the course of reproducibility, the method was found to be extremely poor in durability and completely impossible to reproduce; or the related GC chiral chromatographic column is not in stock at home, and the shelf life is as long as 6 months, thus seriously affecting the efficiency.
Disclosure of Invention
The invention aims to provide an HPLC detection method for separating a palovaried starting material and an enantiomer thereof, which is used for determining the chiral purity ee% value of the palovaried starting material.
The technical scheme adopted by the invention for solving the technical problems is as follows: an HPLC detection method for chiral purity of a paluvirde starting material and an enantiomer thereof comprises the following detection conditions of a chromatographic column: DAICEL CHIRALCEL OD-H, 4.6 x 250mm, 5 μm chiral column, column temperature 20 ℃; mobile phase: isopropyl alcohol: n-hexane = 15: 85(v/v), the optimal separation degree and the flow rate of 1.0 mL/min; elution procedure: isocratic elution with 15% isopropanol for 10-15 min; detection wavelength: 210 nm; comprises the following steps
(1) Taking a proper amount of a palovaried starting material, dissolving a sample by using isopropanol, and preparing a sample solution containing about 3mg of the palovaried starting material in every 1mL of isopropanol;
(2) and (2) injecting the sample solution obtained in the step (1) into a liquid chromatograph according to the sample injection volume of 5 mu L to complete the separation of the Parovirids starting material and the enantiomer thereof, and detecting and recording a chromatogram so as to detect the ee% value of chiral purity.
Furthermore, the chromatographic column is a coating type polysaccharide derivative chiral column.
Further, the column is a column in which a stationary phase surface is coated with cellulose-tris (3, 5-dimethylphenylcarbamate) spherical silica gel.
Further, the isocratic elution proportion is isopropanol: .
Further, the liquid chromatograph is a Thermo Ultimate 3000, DAD detector.
The invention has the beneficial effects that:
the invention adopts DAICEL CHIRALCEL OD-H, 4.6 x 250mm, 5 μm chiral column, not only improves the symmetry of chromatographic peak, but also can effectively separate the starting materials of Parovirids and the enantiomers thereof; the column temperature is selected to be 20 ℃, and the analysis time is shortened.
According to the invention, the isopropanol is selected to dissolve the sample, so that the possibility that the sample solution is separated out from the nonpolar mobile phase n-hexane with a high proportion can be effectively avoided.
The sample injection volume of the invention is 5 mu L, the volume can be properly adjusted according to the concentration of the sample, the flow rate is selected to be 1.0mL/min, and the analysis time and the consumption of the reagent are effectively saved.
The method can simply, quickly and accurately measure the ee% value of chiral purity of the palovaried starting material, and solves the separation problem of the palovaried starting material and enantiomers thereof, thereby ensuring the accurate reliability of the ee% value of the chemical purity of the palovaried starting material.
Drawings
FIG. 1 is a CHIRALCEL IG elution HPLC plot of comparative example 1 of the present invention;
FIG. 2 is a CHIRALCEL OD-H elution HPLC plot of comparative example 2 of the present invention;
FIG. 3 is a CHIRALCEL OD-H elution HPLC chart of comparative example 3 of the present invention.
Detailed Description
The invention is further described with reference to the following figures and specific embodiments.
The applicant finds that by using a coating type polysaccharide derivative chiral column and using n-hexane/isopropanol as a mobile phase system, isocratic elution can effectively separate a paluvirde starting material and an enantiomer thereof, so that the chiral purity ee% value of the paluvirde starting material can be accurately measured.
The HPLC detection method can be realized according to the following method:
(1) taking a proper amount of the palivirtide starting material racemate, dissolving the palivirtide starting material racemate by using isopropanol, and preparing a sample solution containing about 3mg of the palivirtide starting material in every 1mL of isopropanol.
(2) The flow rate of the mobile phase is set to be 1.0mL/min, the detection wavelength is 210nm, and the column temperature of the chromatographic column is 20 ℃.
(3) Injecting 5 mu L of the sample solution in the step (1) into a liquid chromatograph to complete the separation of the starting materials of the paluweide and the enantiomer thereof, thereby detecting the ee% value of chiral purity.
Wherein the detection conditions are as follows:
high performance liquid chromatograph: thermo Ultimate 3000, DAD detector;
and (3) chromatographic column: DAICEL CHIRALCEL OD-H, 4.6 x 250mm, 5 μm chiral column;
mobile phase: n-hexane (channel one), isopropanol (channel two);
elution procedure: eluting with 15% isopropanol for 15 min;
detection wavelength: 210 nm;
flow rate: 1.0 mL/min;
column temperature: 20 ℃;
sample introduction volume: 5 μ L.
The invention adopts a common OD-H chromatographic column and a common neutral reagent to realize separation, and the preparation method is simple and easy to operate, so that the efficiency of chiral quality control of the starting material is obviously improved.
Comparative example 1
Instruments and conditions:
high performance liquid chromatograph: thermo Ultimate 3000, DAD detector;
a chromatographic column: DAICEL CHIRALCEL IG, 4.6 × 250mm, 5 μm chiral column;
mobile phase: n-hexane (channel one), isopropanol (channel two);
elution procedure: eluting with 15% isopropanol for 15 min;
detection wavelength: fully sweeping;
flow rate: 1.0 mL/min;
column temperature: 20 ℃;
sample introduction volume: 5 μ L.
The experimental steps are as follows:
taking 30mg of racemate of directionally synthesized Parovide starting material, placing the racemate in a 10mL volumetric flask, adding isopropanol to dissolve and dilute the racemate to a scale, and shaking up the racemate to be used as a sample solution for developing the method.
And taking the sample solution, carrying out high performance liquid chromatography analysis according to the conditions, and recording a chromatogram. The results are shown in figure 1, wherein the peak 1 in figure 1 is the starting material of palovir and the peak 2 is the peak of its enantiomer, and it can be seen from the figure that under the condition, the starting material of palovir and its enantiomer can not be effectively separated, and the tailing phenomenon exists.
Comparative example 2
Instruments and conditions:
high performance liquid chromatograph: thermo Ultimate 3000, DAD detector;
a chromatographic column: DAICEL CHIRALCEL OD-H, 4.6 x 250mm, 5 μm chiral column;
mobile phase: n-hexane (channel one), isopropanol (channel two);
elution procedure: eluting with 20% isopropanol for 15 min;
detection wavelength: fully sweeping;
flow rate: 1.0 mL/min;
column temperature: 20 ℃;
sample introduction volume: 5 μ L.
The experimental steps are as follows:
taking 30mg of racemate of directionally synthesized Parovide starting material, placing the racemate in a 10mL volumetric flask, adding isopropanol to dissolve and dilute the racemate to a scale, and shaking up the racemate to be used as a sample solution for developing the method.
And taking the sample solution, carrying out high performance liquid chromatography analysis according to the conditions, and recording a chromatogram. The results are shown in figure 2, wherein peak 1 in figure 2 is the paroxetine starting material, and peak 2 is the enantiomer peak, and it can be seen from the figure that under the condition, the separation degree of the paroxetine starting material and the enantiomer thereof is obviously improved, but peak 2 has an enveloped peak.
Comparative example 3
Instruments and conditions:
high performance liquid chromatograph: thermo Ultimate 3000, DAD detector;
a chromatographic column: DAICEL CHIRALCEL OD-H, 4.6 x 250mm, 5 μm chiral column;
mobile phase: n-hexane (channel one), isopropanol (channel two);
elution procedure: eluting with 15% isopropanol for 15 min;
detection wavelength: 210 nm;
flow rate: 1.0 mL/min;
column temperature: 20 ℃;
sample introduction volume: 5 μ L.
The experimental steps are as follows:
taking 30mg of racemate of directionally synthesized Parovide starting material, placing the racemate in a 10mL volumetric flask, adding isopropanol to dissolve and dilute the racemate to a scale, and shaking up the racemate to be used as a sample solution for developing the method.
And taking the sample solution, carrying out high performance liquid chromatography analysis according to the conditions, and recording a chromatogram. The result is shown in figure 3, wherein peak 1 in figure 3 is the starting material of palivirdine, and peak 2 is the peak of enantiomer, and it can be seen from the figure that, under the condition, the starting material of palivirdine is completely separated from enantiomer, and the chromatographic peak included in peak 2 is also eluted, so that the content of enantiomer can be detected more accurately. The main peak of the starting material of the palofurt is about 4.5 min.
The above-described embodiments are merely illustrative of the principles and effects of the present invention, and some embodiments may be applied, and it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the inventive concept of the present invention, and these embodiments are within the scope of the present invention.
Claims (5)
1. An HPLC detection method for chiral purity of a palovaried starting material and an enantiomer thereof is characterized in that the detection conditions are as follows:
a chromatographic column: DAICEL CHIRALCEL OD-H, 4.6 × 250mm, 5 μm chiral column, column temperature 20 deg.C;
mobile phase: isopropyl alcohol: n-hexane = 15: 85(v/v), flow rate 1.0 mL/min;
elution procedure: isocratic elution for 10-15 min;
detection wavelength: 210 nm;
the method comprises the following steps:
(1) dissolving a palovir initial material by using isopropanol to prepare a sample solution;
(2) injecting 5 mu L of sample solution into a liquid chromatograph to complete the separation of the starting materials of the paluweide and the enantiomers thereof, and detecting the ee% value of chiral purity.
2. The chiral purity HPLC method of paroxetine and starting material of paroxetine of claim 1, wherein said sample solution contains 3mg of paroxetine starting material per 1mL of isopropanol.
3. An HPLC detection method of chiral purity of a paroxetine and its enantiomer as claimed in claim 1, wherein the chromatographic column is a coated polysaccharide derivative chiral column.
4. An HPLC detection method of chiral purity of a paroxetine and its enantiomer as claimed in claim 3, wherein the chromatographic column is a spherical silica gel chromatographic column with a stationary phase surface coated with cellulose-tris (3, 5-dimethylphenylcarbamate).
5. An HPLC detection method of chiral purity of a paroxetine starting material and its enantiomer according to any one of claims 1 to 4, wherein the liquid chromatograph is a Thermo Ultimate 3000, DAD detector.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210142617.1A CN114544810A (en) | 2022-02-16 | 2022-02-16 | HPLC detection method for chiral purity of paluvird starting material and enantiomer thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210142617.1A CN114544810A (en) | 2022-02-16 | 2022-02-16 | HPLC detection method for chiral purity of paluvird starting material and enantiomer thereof |
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| CN202210142617.1A Pending CN114544810A (en) | 2022-02-16 | 2022-02-16 | HPLC detection method for chiral purity of paluvird starting material and enantiomer thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435532A (en) * | 2013-09-02 | 2013-12-11 | 苏州永健生物医药有限公司 | Synthetic method of boceprevir intermediate |
| WO2013190509A2 (en) * | 2012-06-22 | 2013-12-27 | Dr.Reddys Laboratories Limited | Preparation of intermediates of boceprevir |
| WO2014061034A1 (en) * | 2012-10-18 | 2014-04-24 | Msn Laboratories Limited | Process for preparation of boceprevir and intermediates thereof |
| CN105330589A (en) * | 2015-11-16 | 2016-02-17 | 江苏大学 | Preparation method of boceprevir intermediate |
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2022
- 2022-02-16 CN CN202210142617.1A patent/CN114544810A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013190509A2 (en) * | 2012-06-22 | 2013-12-27 | Dr.Reddys Laboratories Limited | Preparation of intermediates of boceprevir |
| WO2014061034A1 (en) * | 2012-10-18 | 2014-04-24 | Msn Laboratories Limited | Process for preparation of boceprevir and intermediates thereof |
| CN103435532A (en) * | 2013-09-02 | 2013-12-11 | 苏州永健生物医药有限公司 | Synthetic method of boceprevir intermediate |
| CN105330589A (en) * | 2015-11-16 | 2016-02-17 | 江苏大学 | Preparation method of boceprevir intermediate |
Non-Patent Citations (3)
| Title |
|---|
| NAGARAJU RAJANA ET AL.: "Absolute Configuration of Boceprevir Chiral fragment-B by Chiral Chromatographic, Spectroscopic, Thermal and Crystallization Techniques.", ASIAN JOURNAL OF RESEARCH IN CHEMISTRY, pages 672 * |
| 梁鑫;展鹏;刘新泳;: "波西普韦合成路线图解", 中国医药工业杂志, no. 12 * |
| 马红燕等: "现代分析测试技术与实验", 31 December 2012, 陕西科学技术出版社, pages: 234 * |
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