CN115792026B - Method for detecting enantiomer and diastereomer of larrotib - Google Patents
Method for detecting enantiomer and diastereomer of larrotib Download PDFInfo
- Publication number
- CN115792026B CN115792026B CN202211596173.5A CN202211596173A CN115792026B CN 115792026 B CN115792026 B CN 115792026B CN 202211596173 A CN202211596173 A CN 202211596173A CN 115792026 B CN115792026 B CN 115792026B
- Authority
- CN
- China
- Prior art keywords
- mobile phase
- enantiomer
- impurity
- larotinib
- diastereomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Treatment Of Liquids With Adsorbents In General (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for detecting an enantiomer and a diastereomer of larrotinib, which uses a chromatographic column with a polysaccharide derivative coating type as a filling agent as a chiral chromatographic column, uses a mixed solution of lower alkane and lower alcohol as a mobile phase, and carries out separation and determination on the enantiomer and the diastereomer of larrotinib by a high performance liquid chromatography and an ultraviolet detector; according to the invention, the detection result is optimized by comprehensively considering the comprehensive influence of the analysis column, the mobile phase, the gradient elution program, the flow rate and the column Wen Duifen separation detection, the enantiomer and the diastereoisomer in the larotinib can be rapidly and efficiently separated under the same chromatographic condition, and the detection method has the advantages of high sensitivity, strong specificity, rapidness, convenience and convenience, is convenient to operate, can effectively control the quality of medicines, and is suitable for separating and detecting the enantiomer and the diastereoisomer of the larotinib.
Description
Technical Field
The invention relates to the technical field of analytical chemistry, in particular to a method for separating and measuring a larrotinib enantiomer and diastereoisomer by using HPLC.
Background
Larrotib (Larotrectinib, trade name Vitrakvi), a targeted tropomyosin kinase (tropomyosinrelatedkinase, TRK) antitumor drug developed jointly by Loxo Oncology company and germany bayer company, was approved by the FDA in the united states for use in the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors of the NTRK gene fusion, and is a broad-spectrum antitumor targeted drug with consistent efficacy in a variety of tumors including lung cancer, melanoma, colorectal cancer, gastrointestinal stromal tumor, breast cancer, osteosarcoma, cholangiocarcinoma, soft tissue sarcoma, salivary gland tumor, infant fibrosarcoma, thyroid cancer, primary unknown cancer, congenital mesodermal renal cancer, appendicular cancer and pancreatic cancer.
Larotinib is an inhibitor of the NTRK genes, the NTRK gene family including NTRK1, NTRK2 and NTRK3, which if fused to other genes can lead to aberrant activation, thereby causing the occurrence of tumors. NTRK gene fusion is found in a variety of tumors, with larotinib being the first choice for treatment of such tumors.
Larrotinib formula: c 21H22F2N6O2·H2SO4, molecular weight: 526.51, the chemical structural formula is shown as the following formula (1):
Larotinib has two chiral centers and is synthesized chemically from starting material 1: (S) -2- (2, 5-difluorophenyl) pyrrolidine D (+) -malic acid, formula: molecular weight of C 10H11F2N·C4H6O5: 317.29, a chemical structural formula is shown as the following formula (2); starting material 2: (S) -3-hydroxypyrrolidine, formula: molecular weight of C 4H9 NO: 87.12, wherein each of the chemical structural formulas (3) is introduced with a chiral center.
Larotinib has two chiral centers and is prone to one enantiomer and a pair of diastereomeric impurities during the synthesis and preparation. The impurity structure is as follows:
TABLE 1
The three isomer impurities are commonly existed in the sample and are listed as process impurities of the larotinib, so that the quality of the larotinib bulk drug and the preparation products thereof is affected; meanwhile, the larrotib and the isomer impurities thereof are difficult to separate and detect in the detection process. The detection of the larotinib isomer is not currently reported in the literature.
The invention provides a method for detecting a larrotinib enantiomer and a diastereoisomer by using a polysaccharide derivative coated chiral chromatographic column as a filler and adopting high-performance liquid phase separation.
Disclosure of Invention
In order to accurately reflect the content of enantiomer in the larrotib crude drug or preparation, reasonable basis can be provided for the establishment of quality standard, so that the quality of the product can be better controlled and mastered, and the safety of clinical medication is improved. The detection method has the advantages of good separation degree, high sensitivity and simple method, and is suitable for detection and quality control of the Larotigotine isomer in the pharmaceutical industry.
The technical scheme adopted by the invention is as follows:
The invention provides a method for detecting a larrotigotine enantiomer and diastereoisomer, which uses a chromatographic column with a polysaccharide derivative coating as a filler as a chiral chromatographic column, uses a mixed solution of lower alkane and lower alcohol as a mobile phase, and performs separation and determination on the larrotigotine enantiomer and diastereoisomer by a high performance liquid chromatography and an ultraviolet detector.
Using amylose-tri (3, 5-dimethyl phenyl carbamate) coated on the surface of silica gel as a filler; mixing lower alkane and lower alcohol as mobile phase, and isocratic eluting; the flow rate is 0.6-1.0 ml/min, the column temperature is 30-40 ℃, and the detection is carried out by adopting an ultraviolet detector, wherein the detection wavelength of the ultraviolet detector is 255-264 nm.
The filler is amylose-tri (3, 5-dimethylphenyl carbamate) coated on the surface of silica gel
The chiral chromatographic column is selected from a large xylonite AD-H columnAD-H(250×4.6mm，5μm))。
The lower alkane is n-hexane.
The lower alcohol is methanol, absolute ethanol or a combination thereof; preferably, the volume ratio of the absolute ethanol to the methanol (20:1-100:0) is the absolute ethanol-methanol (24:1)
The mobile phase is the mixing ratio of lower alkane and lower alcohol, n-hexane- [ absolute ethanol-methanol (24:1) ] (85:15-89:11), and preferably n-hexane- [ absolute ethanol-methanol (24:1) ] (87.5:12.5)
The flow rate is 0.6 to 0.8ml/min, preferably 0.7ml/min.
The column temperature is 30-40 ℃, preferably 35 ℃.
The detection wavelength of the ultraviolet detector is 254-264 nm, and the maximum absorption of the ultraviolet detector is 259nm after ultraviolet scanning, so that the temperature of 259 ℃ is preferable.
The beneficial effects of the invention are as follows:
According to the method for detecting the enantiomer and the diastereomer of the larrotigotine, provided by the invention, the detection result is optimized by comprehensively considering the comprehensive influences of the analysis column, the mobile phase, the gradient elution program, the flow rate and the column Wen Duifen separation detection, the enantiomer and the diastereomer in the larrotigotine can be rapidly and efficiently separated under the same chromatographic condition, and the detection method has the advantages of high sensitivity, strong specificity, rapidness, simplicity and convenience, convenience in operation, capability of effectively controlling the quality of medicines and suitability for separating and detecting the enantiomer and the diastereomer of the larrotigotine.
In the existing separation technology, normal phase chromatography is generally adopted for enantiomer detection, reverse phase chromatography is generally adopted for diastereoisomer detection, and two methods are generally adopted for analysis and detection of the three impurities. Compared with the prior art, the invention has remarkable technical progress, and can rapidly and efficiently separate and detect the enantiomer and diastereomer in the larotinib under the same chromatographic condition.
Drawings
FIG. 1 is a chromatogram of a blank solution tested under the conditions of example 1 in the present invention;
FIG. 2 is a chromatogram of a system applicability solution according to the condition of example 1 in the present invention;
FIG. 3 is a chromatogram of a test solution tested according to the conditions of example 1 in the present invention;
FIG. 4 is a chromatogram of a quantitative limiting solution tested under the conditions of example 1 in the present invention;
FIG. 5 is a chromatogram of a detection limit solution according to the condition of example 1 in the present invention;
FIG. 6 is a chromatogram of a system-adapted solution (column temperature-30 ℃ C.) tested according to the conditions of example 2 in the present invention;
FIG. 7 is a chromatogram of a system-adapted solution (column temperature-40 ℃ C.) tested according to the conditions of example 2 in the present invention;
FIG. 8 is a chromatogram of a test solution (mobile phase ratio-n-hexane- [ ethanol-methanol) (24:1) ] (85:15)) detected under the conditions of example 3 in the present invention;
FIG. 9 is a chromatogram of a test solution (mobile phase ratio-n-hexane- [ ethanol-methanol) (24:1) ] (89:11)) detected under the conditions of example 3 in the present invention;
FIG. 10 is a chromatogram of a test solution (combination of lower alcohols-absolute ethanol-methanol (20:1)) tested under the conditions of example 4 in the present invention;
FIG. 11 is a chromatogram of a test solution (combination of lower alcohols-absolute ethanol-methanol (100:0)) tested under the conditions of example 4 in the present invention;
FIG. 12 is a chromatogram of a test solution (flow rate-0.6 ml/min) of the present invention tested under the conditions of example 5;
FIG. 13 is a chromatogram of a test solution (flow rate-0.8 ml/min) of the present invention tested under the conditions of example 5;
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the present invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications could be made by those skilled in the art without departing from the inventive concept. These are all within the scope of the present invention. The reagents and apparatus used were not manufacturer-specific and conventional products were commercially available.
The Larotigotine intermediates and the impurity reference substances used in the embodiment of the invention are all self-made by the inventor.
Example 1
The chromatographic conditions were as follows:
chromatographic column: CHIRALPAK AD-H column (4.6 mm. Times.250 mm 5 μm)
Mobile phase: n-hexane- [ absolute ethanol-methanol) (24:1) ] (87.5:12.5)
Column temperature: 35 DEG C
Flow rate: 0.7ml/min
Detection wavelength: 259nm of
Sample injection amount: 5 μl
Preparing a solution:
Impurity control stock solution: taking about 12.5mg of each of the impurity A reference substance, the impurity B reference substance and the impurity C reference substance, precisely weighing, placing into the same 50ml measuring flask, adding absolute ethyl alcohol for dissolving and diluting to scale, and shaking uniformly to obtain the product.
System applicability solution: and (3) taking about 25mg of Larotinib working reference substance, precisely weighing, placing in a10 ml measuring flask, precisely adding 1ml of the impurity reference substance stock solution into the 10ml measuring flask, adding absolute ethyl alcohol to dissolve and dilute to a scale, and shaking uniformly to obtain the Larotinib working reference substance.
Test solution: about 25mg of Larotigotine is taken, precisely weighed, placed in a 10ml measuring flask, dissolved and diluted to a scale by adding absolute ethyl alcohol, and shaken well.
Quantitative limiting solution: adding the accurate impurity reference stock solution into a measuring flask with 1ml to 100ml of absolute ethyl alcohol, diluting to a scale, shaking uniformly, accurately measuring 4ml to 10ml, diluting to a scale with absolute ethyl alcohol, and shaking uniformly to obtain the product.
Detection limit solution: precisely measuring 5ml of the quantitative limiting solution, placing in a 10ml measuring flask, adding a diluent to dilute to a scale, and shaking uniformly to obtain the product.
And (3) measuring: and respectively injecting a blank solution (absolute ethyl alcohol), a system applicability solution, a test sample solution, a quantitative limit solution and a detection limit solution into a high performance liquid chromatograph for detection, and recording a chromatogram.
The chromatograms of the blank solution, the system applicability solution, the sample solution, the quantitative limit solution and the detection limit solution are respectively shown in fig. 1,2, 3, 4 and 5, and as can be seen, fig. 1 shows that the blank does not interfere with impurity inspection; FIG. 2 shows that the degree of separation between each impurity and the Larotigotine is good, and the specific Larotigotine system applicability spectrum data are shown in Table 2; FIG. 3 shows that impurity C (0.012 wt.%), impurity B (0.13 wt.%), and no impurity A were detected in the self-made Larottinib sample, and that the detected impurity B, C was below 0.15 wt.%; FIG. 4 shows that the quantitative limits of impurity A, impurity B and impurity C are 0.04wt%, 0.04wt% and 0.04wt%, respectively; FIG. 5 shows that the detection limits of Larotigotine and impurity A, impurity B and impurity C are 0.02wt%, 0.02wt% and 0.02wt%, respectively, below the limits of 0.15wt% for each impurity; the method has high detection sensitivity.
Table 2 table of suitability of Larotigotine System in example 1
| Sample of | Retention time (min) | Peak area | Degree of separation | Number of theoretical plates |
| Impurity A | 41.642 | 640.411 | —— | 10933 |
| Impurity C | 44.572 | 611.054 | 1.75 | 10226 |
| Larotinib | 48.085 | 60992.588 | 1.88 | 9494 |
| Impurity B | 52.084 | 633.971 | 2.04 | 11535 |
Example 2
The same chromatographic column, mobile phase and flow rate as in example 1 were used, and only the column temperature was different, and impurity A, impurity B and impurity C of larrotinib were separately detected at 30℃and 40 ℃.
The chromatographic conditions were as follows:
chromatographic column: CHIRALPAK AD-H column (4.6 mm. Times.250 mm 5 μm)
Mobile phase: n-hexane- [ absolute ethanol-methanol) (24:1) ] (87.5:12.5)
Column temperature: 30 ℃/40 DEG C
Flow rate: 0.7ml/min
Detection wavelength: 259nm of
Sample injection amount: 5 μl
Preparing a solution:
Impurity control stock solution: taking about 12.5mg of each of the impurity A reference substance, the impurity B reference substance and the impurity C reference substance, precisely weighing, placing into the same 50ml measuring flask, adding absolute ethyl alcohol for dissolving and diluting to scale, and shaking uniformly to obtain the product.
System applicability solution: and (3) taking about 25mg of Larotinib working reference substance, precisely weighing, placing in a10 ml measuring flask, precisely adding 1ml of the impurity reference substance stock solution into the 10ml measuring flask, adding absolute ethyl alcohol to dissolve and dilute to a scale, and shaking uniformly to obtain the Larotinib working reference substance.
And (3) measuring: and (5) injecting the system applicability solution into a high performance liquid chromatograph, and recording a chromatogram. See fig. 6 and 7.
The results show that under the chromatographic conditions, the baseline is stable, the separation degree among the larrotib, the impurity A, the impurity B and the impurity C is not obviously different from that of the example 1, and the baseline separation of four substances can be realized within 30-40 ℃. The chromatographic separation is most preferably carried out at a column temperature of 35 ℃ by combining factors such as analysis time, the use temperature range (0-40 ℃) of the chromatographic column and the like.
Table 3 table of suitability of larotinib system (different column temperatures) data in example 2
Example 3
The same chromatographic column as in example 1 was used, the column temperature, flow rate and mobile phase were changed only by changing the ratio of the mobile phase, and impurity A, impurity B and impurity C of larrotinib were detected by separation under the conditions of mobile phase n-hexane- [ absolute ethanol-methanol (24:1) ] (85:15), n-hexane- [ absolute ethanol-methanol (24:1) ] (89:11).
The chromatographic conditions were as follows:
chromatographic column: CHIRALPAK AD-H column (4.6 mm. Times.250 mm 5 μm)
Mobile phase: n-hexane- [ absolute ethanol-methanol) (24:1) ] (85:15)/n-hexane- [ absolute ethanol-methanol (24:1) ] (89:11)
Column temperature: 35 DEG C
Flow rate: 0.7ml/min
Detection wavelength: 259nm of
Sample injection amount: 5 μl
Preparing a solution:
Impurity control stock solution: taking about 12.5mg of each of the impurity A reference substance, the impurity B reference substance and the impurity C reference substance, precisely weighing, placing into the same 50ml measuring flask, adding absolute ethyl alcohol for dissolving and diluting to scale, and shaking uniformly to obtain the product.
System applicability solution: and (3) taking about 25mg of Larotinib working reference substance, precisely weighing, placing in a10 ml measuring flask, precisely adding 1ml of the impurity reference substance stock solution into the 10ml measuring flask, adding absolute ethyl alcohol to dissolve and dilute to a scale, and shaking uniformly to obtain the Larotinib working reference substance.
And (3) measuring: and (5) injecting the system applicability solution into a high performance liquid chromatograph, and recording a chromatogram. See fig. 9, 10.
The results show that under the chromatographic conditions, the baseline is stable, the separation degree of the impurity C and the impurity B is reduced along with the reduction of the proportion of the n-hexane, and the baseline separation of four substances can be realized in mobile phase n-hexane- [ ethanol-methanol (24:1) ] (85:15-89:11). The most preferred mobile phase of the invention is chromatographic separation under the condition of n-hexane- [ ethanol-methanol (24:1) ] (87.5:12.5), and the like by combining the factors of the separation degree, the analysis time and the like.
Table 4 table of suitability profile (mobile phase ratio) data for larotinib system in example 3
Example 4
Using the same column as in example 1, the column temperature, flow rate, and mobile phase ratio were changed only to the lower alcohol composition in the mobile phase, and impurity A, impurity B, and impurity C of Larotinib were detected by separation under the conditions of mobile phase n-hexane- [ absolute ethanol-methanol (20:1) ] (87.5:12.5), and n-hexane-absolute ethanol (87.5:12.5), respectively.
The chromatographic conditions were as follows:
chromatographic column: CHIRALPAK AD-H column (4.6 mm. Times.250 mm 5 μm)
Mobile phase: n-hexane- [ absolute ethanol-methanol (20:1) ] (87.5:12.5), n-hexane-absolute ethanol (87.5:12.5)
Column temperature: 35 DEG C
Flow rate: 0.7ml/min
Detection wavelength: 259nm of
Sample injection amount: 5 μl
Preparing a solution:
Impurity control stock solution: taking about 12.5mg of each of the impurity A reference substance, the impurity B reference substance and the impurity C reference substance, precisely weighing, placing into the same 50ml measuring flask, adding absolute ethyl alcohol for dissolving and diluting to scale, and shaking uniformly to obtain the product.
System applicability solution: and (3) taking about 25mg of Larotinib working reference substance, precisely weighing, placing in a10 ml measuring flask, precisely adding 1ml of the impurity reference substance stock solution into the 10ml measuring flask, adding absolute ethyl alcohol to dissolve and dilute to a scale, and shaking uniformly to obtain the Larotinib working reference substance.
And (3) measuring: and (5) injecting the system applicability solution into a high performance liquid chromatograph, and recording a chromatogram. See fig. 9, 10.
The results show that under the chromatographic conditions, the baseline is stable, the separation degree of the impurity A and the impurity C and the separation degree of the impurity B in the lower alcohol in the mobile phase are increased along with the increase of the proportion of the methanol, the separation degree of the impurity C and the impurity B is reduced, and the baseline separation of four substances can be realized in the combined absolute ethyl alcohol-methanol (20:1-100:0) of the lower alcohol in the mobile phase. Considering that all four materials have the proper degree of separation, the most preferred combination of lower alcohols in the mobile phase of the present invention is absolute ethanol-methanol (24:1).
TABLE 5 data sheet for the suitability of Larottinib System (combination of lower alcohols) in example 4
Example 5
The same chromatographic column as in example 1 was used, the column temperature and the mobile phase ratio were changed only at the flow rate, and the impurity A, impurity B and impurity C of larrotinib were separately detected under the conditions of the flow rate of 0.6ml/min and 0.8ml/min, respectively.
The chromatographic conditions were as follows:
chromatographic column: CHIRALPAK AD-H column (4.6 mm. Times.250 mm 5 μm)
Mobile phase: n-hexane- [ absolute ethanol-methanol) (24:1) ] (87.5:12.5)
Column temperature: 35 DEG C
Flow rate: 0.6ml/min/0.8ml/min
Detection wavelength: 259nm of
Sample injection amount: 5 μl
Preparing a solution:
Impurity control stock solution: taking about 12.5mg of each of the impurity A reference substance, the impurity B reference substance and the impurity C reference substance, precisely weighing, placing into the same 50ml measuring flask, adding absolute ethyl alcohol for dissolving and diluting to scale, and shaking uniformly to obtain the product.
System applicability solution: and (3) taking about 25mg of Larotinib working reference substance, precisely weighing, placing in a10 ml measuring flask, precisely adding 1ml of the impurity reference substance stock solution into the 10ml measuring flask, adding absolute ethyl alcohol to dissolve and dilute to a scale, and shaking uniformly to obtain the Larotinib working reference substance.
And (3) measuring: and (5) injecting the system applicability solution into a high performance liquid chromatograph, and recording a chromatogram. See fig. 9, 10.
The results show that under the chromatographic conditions, the baseline is stable, and the separation degree of the impurity A and the impurity C and the separation degree of the impurity B are reduced along with the increase of the flow rate, and the baseline separation of four substances can be realized within the flow rate (0.6 ml/min-0.8 ml/min). The most preferred flow rate of the present invention is 0.7ml/min, combining the factors of separation degree and analysis time.
Table 6 table of suitability of Larottinib System (different flow rates) data in example 5
The above examples are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solution of the present invention should fall within the scope of protection defined by the claims of the present invention without departing from the spirit of the present invention.
Claims (6)
1. A method for detecting the enantiomer and diastereomer of the larotinib is characterized in that the separation and the determination of the enantiomer and the diastereomer of the larotinib are carried out by a high performance liquid chromatography method by an ultraviolet detector;
Chromatographic conditions: the chromatographic column with amylose-tris (3, 5-dimethylphenylcarbamate) coated on the surface of silica gel as a filler is used as a chiral chromatographic column, a mobile phase is composed of a mobile phase A and a mobile phase B, the mobile phase A is n-hexane, the mobile phase B is composed of absolute ethyl alcohol and methanol in a volume ratio of 20:1 or 24:1 or 100:0, the mixing ratio of the mobile phase A and the mobile phase B is 85:15 or 87.5:12.5 or 89:11, the flow rate is 0.6-0.8 ml/min, the column temperature is 30-40 ℃, and the detection wavelength of an ultraviolet detector is 254-264 nm;
The chemical structural formulas of the larrotinib enantiomer and diastereomer are respectively as follows:
；
Preparation of test solution: and (3) taking larotinib, precisely weighing, placing into a measuring flask, adding absolute ethyl alcohol for dissolution, diluting to a scale, and shaking uniformly.
2. The method according to claim 1, wherein the chiral chromatographic column is CHIRALPAK-H, 250 x 4.6mm,5 μm.
3. The method of claim 1, wherein the flow rate is 0.7ml/min.
4. The method of claim 1, wherein the column temperature is 35 ℃.
5. The method of claim 1, wherein the detection wavelength is 259nm.
6. The method according to claim 1, wherein the separation between the larotinib and the four components of enantiomer, diastereomer is > 1.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211596173.5A CN115792026B (en) | 2022-12-13 | 2022-12-13 | Method for detecting enantiomer and diastereomer of larrotib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211596173.5A CN115792026B (en) | 2022-12-13 | 2022-12-13 | Method for detecting enantiomer and diastereomer of larrotib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115792026A CN115792026A (en) | 2023-03-14 |
| CN115792026B true CN115792026B (en) | 2024-06-04 |
Family
ID=85419620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211596173.5A Active CN115792026B (en) | 2022-12-13 | 2022-12-13 | Method for detecting enantiomer and diastereomer of larrotib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115792026B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981779A (en) * | 2019-11-23 | 2020-04-10 | 武汉理工大学 | The synthetic method of R-2-(2,5-difluorophenyl)pyrrolidine |
| WO2020119206A1 (en) * | 2018-12-12 | 2020-06-18 | 上海健康医学院 | Radioactive iodine-labelled larotrectinib compound, preparation method therefor and use thereof |
| CN113307812A (en) * | 2021-07-01 | 2021-08-27 | 郑州大学第一附属医院 | Preparation method of broad-spectrum tumor drug erlotinib |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11998534B2 (en) * | 2020-02-12 | 2024-06-04 | Eubulus Biotherapeutics Inc. | GPX4 inhibitor in combination with anticancer agent for treating proliferative disease |
-
2022
- 2022-12-13 CN CN202211596173.5A patent/CN115792026B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020119206A1 (en) * | 2018-12-12 | 2020-06-18 | 上海健康医学院 | Radioactive iodine-labelled larotrectinib compound, preparation method therefor and use thereof |
| CN110981779A (en) * | 2019-11-23 | 2020-04-10 | 武汉理工大学 | The synthetic method of R-2-(2,5-difluorophenyl)pyrrolidine |
| CN113307812A (en) * | 2021-07-01 | 2021-08-27 | 郑州大学第一附属医院 | Preparation method of broad-spectrum tumor drug erlotinib |
Non-Patent Citations (2)
| Title |
|---|
| Process development of enantioselective imine reductase-catalyzed syntheses of pharmaceutically relevant prrolidines;Laura M. Bernhard 等;DI ORGANIC PROCESS RESEARCH & DEVELOPMENT;20220228;第26卷(第7期);第2067-2074页 * |
| 拉罗替尼合成路线图解;邱献华 等;中国药物化学杂志;20190831;第29卷(第4期);第325-328+250页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115792026A (en) | 2023-03-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114651177A (en) | Carbocisteine raw material and quality control method and application of preparation thereof | |
| CN111208232A (en) | Analysis method of related substances in avanafil and preparation thereof | |
| CN111239299B (en) | Method for separating and measuring palbociclib and impurities thereof | |
| Alwera et al. | RP‐HPLC enantioseparation of β‐adrenolytics using micellar mobile phase without organic solvents | |
| CN106841415B (en) | Analysis method in relation to substance in a kind of Azilsartan raw material and its preparation | |
| CN115792026B (en) | Method for detecting enantiomer and diastereomer of larrotib | |
| Patti et al. | Chiral HPLC analysis of milnacipran and its FMOC‐derivative on cellulose‐based stationary phases | |
| CN107941959B (en) | Liquid chromatography method for separating ezetimibe and optical isomer thereof | |
| CN113884601A (en) | Method for detecting idoxaban tosylate isomer | |
| CN111812228B (en) | Method for measuring metoprolol tartrate and tablet impurities thereof by ultra-high performance liquid chromatography | |
| CN109991319B (en) | Timolol compound and separation method and application of timolol maleate related impurities | |
| CN114965754B (en) | Method for detecting related substances and bacteriostat in acetaminophen tablet | |
| Sornchaithawatwong et al. | Simultaneous determination of paracetamol and its main degradation product in generic paracetamol tablets using reverse-phase HPLC | |
| CN115236255B (en) | Method for detecting related substances of loxoprofen sodium | |
| CN109738536B (en) | Method for separating benzaldehyde and nitrobenzaldehyde by using high performance liquid chromatography | |
| Ali et al. | Synthesis and characterization of novel imino derivatives of acenocoumarol: chiral separation, absolute configuration and determination of biological activity | |
| CN112979511B (en) | A kind of method for analyzing and preparing tert-butyl sulfinamide enantiomer by HPLC | |
| CN110361472B (en) | HPLC detection method of mikui ammonium chloride intermediate MIV-G isomer | |
| CN113945672B (en) | Method for detecting ticagrelor and related substances thereof | |
| CN112630313A (en) | High performance liquid phase resolution method of (S) -3-hydroxytetrahydrofuran enantiomer | |
| CN115856135B (en) | Method for separating and measuring related substances in aximide hydrochloride by using HPLC | |
| CN114062518A (en) | A kind of method for separating and measuring optical isomer content of tartaric acid | |
| CN107656005B (en) | Method for separating and determining erlotinib hydrochloride and potential impurities | |
| CN114280190B (en) | Kit for detecting related substances of double cysteines | |
| CN106442793B (en) | A kind of detection method of the intermediate for preparing Afatinib and its enantiomter |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |