CN113466395B - Method for detecting content of 4-chloro-3-trifluoromethyl isocyanate phenyl in regorafenib and intermediate drug - Google Patents
Method for detecting content of 4-chloro-3-trifluoromethyl isocyanate phenyl in regorafenib and intermediate drug Download PDFInfo
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- CN113466395B CN113466395B CN202110885048.5A CN202110885048A CN113466395B CN 113466395 B CN113466395 B CN 113466395B CN 202110885048 A CN202110885048 A CN 202110885048A CN 113466395 B CN113466395 B CN 113466395B
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- 239000002138 L01XE21 - Regorafenib Substances 0.000 title claims abstract description 20
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960004836 regorafenib Drugs 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 229940079593 drug Drugs 0.000 title claims abstract description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 59
- 239000000243 solution Substances 0.000 claims abstract description 17
- NBJZEUQTGLSUOB-UHFFFAOYSA-N 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(N=C=O)=CC=C1Cl NBJZEUQTGLSUOB-UHFFFAOYSA-N 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001514 detection method Methods 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000007865 diluting Methods 0.000 claims abstract description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010828 elution Methods 0.000 claims abstract description 9
- 238000001819 mass spectrum Methods 0.000 claims abstract description 9
- 239000000523 sample Substances 0.000 claims abstract description 9
- 239000012488 sample solution Substances 0.000 claims abstract description 8
- 239000013558 reference substance Substances 0.000 claims abstract description 7
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000019253 formic acid Nutrition 0.000 claims abstract description 5
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 239000000945 filler Substances 0.000 claims abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 3
- 238000011068 loading method Methods 0.000 claims abstract description 3
- 238000001035 drying Methods 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 3
- 238000004949 mass spectrometry Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 238000001212 derivatisation Methods 0.000 abstract description 4
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- 239000011550 stock solution Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- 238000005303 weighing Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 208000016676 colorectal gastrointestinal stromal tumor Diseases 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- -1 phenyl chloro-3-trifluoromethylacrylate Chemical compound 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
- G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
- G01N30/724—Nebulising, aerosol formation or ionisation
- G01N30/7266—Nebulising, aerosol formation or ionisation by electric field, e.g. electrospray
-
- 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
-
- 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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/067—Preparation by reaction, e.g. derivatising the sample
Abstract
The invention relates to a method for detecting the content of 4-chloro-3-trifluoromethyl isocyanate phenyl in regorafenib and an intermediate drug, which comprises the following steps: step one, taking a regorafenib sample, taking isopropanol as a solvent to prepare a sample solution, and dissolving and diluting 4-chloro-3-trifluoromethyl phenyl isocyanate with isopropanol to prepare a reference substance solution; step two, performing high performance liquid chromatography by taking octadecylsilane chemically bonded silica as a filler, taking formic acid aqueous solution as a mobile phase A and methanol as a mobile phase B, and loading the sample for gradient elution; and thirdly, performing mass spectrum detection by adopting a mass spectrum detector. The invention uses the high performance liquid chromatography-mass spectrometer to detect, and meanwhile, the isopropanol as the solvent and the derivatization agent has the characteristics of good derivatization effect, high sensitivity, good accuracy, good repeatability and the like, and can be widely used for analyzing and detecting the content of 4-chloro-3-trifluoromethyl isocyanate in regorafenib and intermediate medicaments.
Description
Technical Field
The embodiment of the invention belongs to the technical field of analysis and detection of regorafenib and intermediate medicaments, and particularly relates to a method for detecting the content of 4-chloro-3-trifluoromethyl phenyl isocyanate in regorafenib and intermediate medicaments.
Background
Regorafenib is a novel oral multi-target protein kinase inhibitor, can block proliferation of tumor cells, inhibit angiogenesis of tumor and regulate and control tumor microenvironment, has good anti-tumor activity, and has been used for treating advanced colorectal cancer, gastrointestinal stromal tumor and hepatocellular carcinoma in batches at present.
Currently, the synthesis of regorafenib generally uses 4-chloro-3-trifluoromethyl-phenyl isocyanate as a raw material, which results in the obtained intermediate and regorafenib possibly having a certain amount of 4-chloro-3-trifluoromethyl-phenyl isocyanate remained.
In order to ensure the purity and activity effects of regorafenib and intermediates, it is important to analyze and control the content of 4-chloro-3-trifluoromethyl phenyl isocyanate in regorafenib and intermediates.
Therefore, there is a need to develop new methods for detecting and analyzing the content of 4-chloro-3-trifluoromethyl-phenyl isocyanate in regorafenib and intermediates.
Disclosure of Invention
After intensive research, the inventor provides a method for detecting the content of 4-chloro-3-trifluoromethyl isocyanate phenyl ester in regorafenib and an intermediate medicament, and the method has the advantages of high sensitivity, good accuracy, good repeatability and the like.
A method for detecting the content of 4-chloro-3-trifluoromethyl isocyanate in regorafenib and intermediate drugs, comprising the following steps:
step one, taking a regorafenib sample, taking isopropanol as a solvent to prepare a sample solution, and taking 4-chloro-3-trifluoromethyl phenyl isocyanate, dissolving and diluting the sample solution with isopropanol to prepare a 4-chloro-3-trifluoromethyl phenyl isocyanate solution serving as a reference substance solution;
step two, performing high performance liquid chromatography by taking octadecylsilane chemically bonded silica as a filler, taking formic acid aqueous solution as a mobile phase A and methanol as a mobile phase B, and loading the sample for gradient elution;
and thirdly, performing mass spectrum detection by adopting a mass spectrum detector.
Preferably, the control solution contains 0.6ng of phenyl 4-chloro-3-trifluoromethylisocyanate per 1 mL.
Preferably, the specification of the octadecylsilane chemically bonded silica is 2.1mm in inner diameter, 100mm in column length and 1.8 μm in particle size.
Preferably, the volume concentration of the formic acid aqueous solution is 0.05%.
Preferably, the column temperature of the gradient elution is 35 ℃, the flow rate is 0.3 mL/min, and the sample injection amount is 5 mu L.
Preferably, the specific process of the gradient elution is as follows:
the time is 0.00 minute, the volume ratio of the mobile phase A is 90 percent, and the volume ratio of the mobile phase B is 10 percent;
the time is 1.20 minutes, the volume ratio of the mobile phase A is 90 percent, and the volume ratio of the mobile phase B is 10 percent;
for 4.00 minutes, the volume ratio of the mobile phase A is 40% and the volume ratio of the mobile phase B is 60%;
the time is 8.00 minutes, the volume ratio of the mobile phase A is 5 percent, and the volume ratio of the mobile phase B is 95 percent;
13.00 minutes, 5% by volume of mobile phase A and 95% by volume of mobile phase B;
13.10 minutes, 90% by volume of mobile phase A and 10% by volume of mobile phase B;
the time was 15.00 minutes, the mobile phase A volume ratio was 90% and the mobile phase B volume ratio was 10%.
Preferably, the mass spectrum detection adopts an electrospray ion source and anion detection mode, the capillary voltage is 3500V, the sheath gas temperature is 250 ℃, the sheath gas flow rate is 11L/min, the atomization gas is 45psi, the drying gas temperature is 300 ℃, and the drying gas flow rate is 5L/min.
Compared with the prior art, the invention has the following beneficial effects:
the invention uses the high performance liquid chromatography-mass spectrometer to detect, and meanwhile, the isopropanol as the solvent and the derivatization agent has good derivatization effect, has the advantages of high sensitivity, good accuracy, good repeatability and the like, and can be widely used for analyzing and detecting the content of 4-chloro-3-trifluoromethyl isocyanate in regorafenib and intermediate medicaments.
Drawings
FIG. 1 is a linear regression diagram of an embodiment of the present invention.
FIG. 2 is a schematic representation of a blank solution according to an embodiment of the present invention.
FIG. 3 is a typical diagram of a control solution according to an embodiment of the present invention.
FIG. 4 is a schematic diagram of a sample solution according to an embodiment of the present invention.
Detailed Description
A method for detecting the content of 4-chloro-3-trifluoromethyl isocyanate phenyl in regorafenib and intermediate medicaments comprises the following steps:
control stock solution: taking about 6mg of 4-chloro-3-trifluoromethyl isocyanate as a reference substance, precisely weighing, placing into a 10mL measuring flask, adding isopropanol to dissolve and dilute to a scale, and shaking uniformly; precisely measuring 0.1mL, placing a 50mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly; precisely measuring 1mL, placing a 10mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly; precisely measuring 1mL, placing in a 20mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly to obtain (about 6 ng/mL);
control Solution (STD): precisely measuring 1mL of reference stock solution, placing in a 10mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly to obtain (0.6 ng/mL);
200% linear solution: precisely measuring 4mL of control stock solution, placing in a 20mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly;
150% linear solution: precisely measuring 3mL of control stock solution, placing in a 20mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly;
100% linear solution: precisely measuring 2mL of control stock solution, placing in a 20mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly;
75% linear solution: precisely measuring 1.5mL of control stock solution, placing in a 20mL measuring flask, adding isopropanol to dilute to scale, and shaking uniformly;
50% linear solution: precisely measuring 1mL of reference stock solution, placing in a 20mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly;
25% linear solution: precisely measuring 0.5mL of control stock solution, placing in a 20mL measuring flask, adding isopropanol to dilute to scale, and shaking uniformly;
LOQ: precisely measuring 0.5mL of control stock solution, placing a 20mL measuring flask, adding isopropanol to dilute to a scale, shaking uniformly, and preparing 6 parts in parallel;
LOD: precisely measuring 1mL of 100% linear solution, placing a 10mL measuring flask, adding isopropanol to dilute to a scale, and shaking uniformly;
test solution: taking about 20mg of the product, precisely weighing, placing into a 20mL measuring flask, dissolving with isopropanol, diluting to a scale, and shaking uniformly; precisely measuring 0.1mL, placing in a 10mL volumetric flask, diluting isopropanol to a scale, shaking uniformly, and preparing 3 parts in parallel;
50% of the labeled test sample solution: taking about 20mg of the product, precisely weighing, placing into a 20mL measuring flask, dissolving with isopropanol, diluting to a scale, and shaking uniformly; precisely measuring 0.1mL, placing in a 10mL volumetric flask, precisely measuring 0.5mL of reference substance stock solution, diluting isopropanol to a scale, shaking uniformly, and preparing 3 parts in parallel;
100% of standard test solution: taking about 20mg of the product, precisely weighing, placing into a 20mL measuring flask, dissolving with isopropanol, diluting to a scale, and shaking uniformly; precisely measuring 0.1mL, placing in a 10mL volumetric flask, precisely measuring 1mL of reference substance stock solution, diluting isopropanol to scale, shaking uniformly, and preparing 6 parts in parallel;
150% of labeled test sample solution: taking about 20mg of the product, precisely weighing, placing into a 20mL measuring flask, dissolving with isopropanol, diluting to a scale, and shaking uniformly; precisely measuring 0.1mL, placing in a 10mL volumetric flask, precisely measuring 1.5mL of reference substance stock solution, diluting isopropanol to a scale, shaking uniformly, and preparing 3 parts in parallel;
octadecylsilane chemically bonded silica is used as a filler (Agilent RRHD C18, the inner diameter is 2.1mm, the column length is 100mm, the particle size is 1.8 mu m), formic acid water with the volume ratio of 0.05% is used as a mobile phase A, methanol is used as a mobile phase B, gradient elution is carried out according to a table 1, the column temperature is 35 ℃, the flow rate is 0.3mL per minute, and the sample injection amount is 5 mu L;
TABLE 1 gradient elution table
| Time (minutes) | Mobile phase a (%) | Mobile phase B (%) |
| 0.00 | 90 | 10 |
| 1.20 | 90 | 10 |
| 4.00 | 40 | 60 |
| 8.00 | 5 | 95 |
| 13.00 | 5 | 95 |
| 13.10 | 90 | 10 |
| 15.00 | 90 | 10 |
The mass spectrum detector is adopted, the mass spectrum method adopts an electrospray ion source (AJS ESI), the negative ion detection mode, the capillary voltage is 3500V, the sheath gas temperature is 250 ℃, the sheath gas flow rate is 11L/min, the atomization gas is 45psi, the drying gas temperature is 300 ℃, and the drying gas flow rate is 5L/min. Mass spectrometry detection of 4-chloro-3-trifluoromethyl-phenyl isocyanate is shown in table 2.
Table 2 4 Mass spectrometric detection of phenyl chloro-3-trifluoromethylacrylate
TABLE 3 Linear results
TABLE 4 quantitative limit and detection limit results
TABLE 5 quantitative limit results
TABLE 6 accuracy results
TABLE 7 repeatability results
TABLE 8 stability results
The method for detecting the content of the 4-chloro-3-trifluoromethyl isocyanate provided by the embodiment uses a high performance liquid chromatography-mass spectrometer for detection, and simultaneously has the advantages of good isopropanol derivative effect as a solvent and a derivative agent, high sensitivity, good accuracy, good repeatability and the like by combining with the table 1-table 8 and the table 1-fig. 4.
Claims (5)
1. A method for detecting the content of 4-chloro-3-trifluoromethyl-phenyl isocyanate in regorafenib and an intermediate drug, comprising the steps of:
step one, taking a regorafenib sample, taking isopropanol as a solvent to prepare a sample solution, and taking 4-chloro-3-trifluoromethyl phenyl isocyanate, dissolving and diluting the sample solution with isopropanol to prepare a 4-chloro-3-trifluoromethyl phenyl isocyanate solution serving as a reference substance solution;
step two, performing high performance liquid chromatography by taking octadecylsilane chemically bonded silica as a filler, taking formic acid aqueous solution as a mobile phase A and methanol as a mobile phase B, and loading the sample for gradient elution;
step three, adopting a mass spectrum detector to carry out mass spectrum detection;
the specific process of the gradient elution is as follows:
the time is 0.00 minute, the volume ratio of the mobile phase A is 90 percent, and the volume ratio of the mobile phase B is 10 percent;
the time is 1.20 minutes, the volume ratio of the mobile phase A is 90 percent, and the volume ratio of the mobile phase B is 10 percent;
for 4.00 minutes, the volume ratio of the mobile phase A is 40% and the volume ratio of the mobile phase B is 60%;
the time is 8.00 minutes, the volume ratio of the mobile phase A is 5 percent, and the volume ratio of the mobile phase B is 95 percent;
13.00 minutes, 5% by volume of mobile phase A and 95% by volume of mobile phase B;
13.10 minutes, 90% by volume of mobile phase A and 10% by volume of mobile phase B;
the time is 15.00 minutes, the volume ratio of the mobile phase A is 90 percent, and the volume ratio of the mobile phase B is 10 percent;
the specification of the octadecylsilane chemically bonded silica gel is 2.1mm in inner diameter, 100mm in column length and 1.8 mu m in particle size.
2. The method of claim 1, wherein the aqueous formic acid solution has a volume concentration of 0.05%.
3. The method of claim 1, wherein the gradient elution is performed at a column temperature of 35 ℃ and a flow rate of 0.3mL per minute, and the sample is introduced at a volume of 5 μl.
4. The method of claim 1, wherein the control solution contains 0.6ng of phenyl 4-chloro-3-trifluoromethylacetate per 1 mL.
5. The method of claim 1, wherein the mass spectrometry is performed using an electrospray ion source and a negative ion detection mode, the capillary voltage is 3500V, the sheath gas temperature is 250 ℃, the sheath gas flow rate is 11L/min, the atomizing gas is 45psi, the drying gas temperature is 300 ℃, and the drying gas flow rate is 5L/min.
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