CN112461971B - Forbitasvir and detection method thereof - Google Patents
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- CN112461971B CN112461971B CN202011310452.1A CN202011310452A CN112461971B CN 112461971 B CN112461971 B CN 112461971B CN 202011310452 A CN202011310452 A CN 202011310452A CN 112461971 B CN112461971 B CN 112461971B
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Abstract
The invention relates to forbitasvir and a verification method thereof, wherein the molecular formula of the forbitasvir is C 43 H 53 N 7 O 7 Molecular weight of 779.92, and name 4- {2- (S) - [ N- ((S) -2-methoxycarbonylamino-3-methylbutyryl) pyrrolidine-2-yl]-1H-imidazol-5-yl } -4' - {4- [ (S) -N- ((S) -2-methoxycarbonylamino-3-methylbutanoyl) pyrrolidin-2-yl]-1H-pyrrolo [3,4-c]Tetrahydrofuran-2-yl } -1,1' -biphenyl, in the form of a powder, calculated as the anhydride, containing C 43 H 53 N 7 O 7 Not less than 97.5%.
Description
Technical Field
The invention relates to the research of fubitasvir, in particular to fubitasvir and a detection method thereof.
Background
The fubitasvir is a novel HCV NS5A inhibitor, and the main action mechanism of the fubitasvir is to prevent the HCV replication by inhibiting NS5A protein so as to achieve the effect of treating chronic hepatitis C. The fubitasvir is prepared by Suzuki coupling reaction of an organic boric acid (ester) compound and an aryl halogen compound.
The design of the fubitavir and the detection method thereof which have low cost and are easy to realize is a technical problem which needs to be solved urgently by the technical personnel in the field.
Disclosure of Invention
The invention aims to provide the fubitazivir and the verification method thereof, wherein the fubitazivir is simple in process flow and low in cost.
In order to solve the technical problem, the invention provides the fubitasvir with the molecular formula of C 43 H 53 N 7 O 7 Molecular weight 779.92, named 4- {2- (S) - [ N- ((S) -2-methoxycarbonylamino-3-methylbutyryl) pyrrolidin-2-yl]-1H-imidazol-5-yl } -4'- {4- [ (S) -N- ((S) -2-methoxycarbonylamino-3-methylbutyryl) pyrrolidin-2-yl]-1H-pyrrolo [3,4-c]Tetrahydrofuran-2-yl } -1,1' -biphenyl, the molecular structural formula of which is shown in I, and the powder of which contains C calculated as anhydride 43 H 53 N 7 O 7 Not less than 97.5%;
the method for detecting the fubitasvir comprises the following steps:
A. detecting impurities by high performance liquid chromatography;
B. performing isomer detection by high performance liquid chromatography;
C. detecting the residual solvent;
D. detecting firing residues and heavy metals;
E. detecting palladium;
F. by potentiometric titration of C 43 H 53 N 7 O 7 And (4) measuring the content.
Further, in the step a, chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler, a 10mmol/L potassium dihydrogen phosphate solution (1.36 g of potassium dihydrogen phosphate is taken, water is added for dissolution and dilution to 1000mL, the pH value is adjusted to 3.0 by phosphoric acid, shaking is carried out uniformly) is used as a mobile phase A, acetonitrile is used as a mobile phase B, linear gradient elution is carried out, the column temperature is 40 ℃, the flow rate is 1mL per minute, and the detection wavelength is 210nm; precisely weighing the fosetyl-pivoxil, adding methanol for dissolving, quantitatively diluting to prepare a solution containing 0.6mg per 1mL, taking 10 mu L of the test solution as a test solution, injecting into a liquid chromatograph, recording a chromatogram, wherein the theoretical plate number is not less than 3000 according to the main peak of the fosetyl-pivoxil, and the tailing factor is not more than 2.0.
Further, in the step B, the chromatographic conditions are as follows: polysaccharide derivative is used as a filling agent; methyl tert-butyl ether-methanol-diethylamine (500; the column temperature is 40 ℃, the flow rate is 0.5mL per minute, the detection wavelength is 340nm, a proper amount of an impurity E reference substance, an impurity F reference substance and a forbizivir reference substance are taken and precisely weighed, a mobile phase is added for dissolving and quantitatively diluting to prepare a solution containing 1 mu g of each impurity E and F and 0.2mg of forbizivir in each 1mL, the solution is taken as a system applicability solution, 20 mu L of the solution is injected into a liquid chromatograph, a chromatogram is recorded, and the separation degree between a main peak and a known adjacent peak is not less than 1.5; precisely weighing the fostaravir, adding a mobile phase for dissolving, quantitatively diluting to prepare a solution containing about 0.2mg per 1mL, taking 20 mu L of the test solution as a test solution, injecting the test solution into a liquid chromatograph, recording a chromatogram, and calculating the content of each impurity according to an area normalization method, wherein the peak areas of the impurities E and F are not more than 5 times (0.5%) of the main peak area.
Further, in the step C, the residual solvent is methanol, ethanol, acetonitrile, dichloromethane, N-hexane, ethyl acetate, tetrahydrofuran, N-dimethylformamide and benzene.
Further, in the step C, precisely weighing 0.2g of fubiziwei, placing the fubiziwei in a headspace bottle, precisely adding 2mL of dimethyl sulfoxide, sealing the headspace bottle, and placing the headspace bottle in hot water to enable the solution in the headspace bottle to be a clear transparent liquid to be used as a test solution; accurately weighing proper amounts of methanol, ethanol, acetonitrile, dichloromethane, N-hexane, ethyl acetate, tetrahydrofuran, N-dimethylformamide and benzene, adding dimethyl sulfoxide for quantitative dilution to prepare a mixed solution containing 0.3mg of methanol, 0.5mg of ethanol, 41 micrograms of acetonitrile, 60 micrograms of dichloromethane, 29 micrograms of N-hexane, 0.5mg of ethyl acetate, 72 micrograms of tetrahydrofuran, 88 micrograms of N, N-dimethylformamide and 0.2 micrograms of benzene in each 1mL of solution, accurately weighing 2mL of solution, placing the solution in a top empty bottle, and sealing the bottle to obtain a reference solution; measuring according to the residual solvent measurement method, and using a capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary liquid as a chromatographic column; the initial temperature is 50 ℃, the temperature is kept for 12min, and then the temperature is increased to 120 ℃ at the rate of 40 ℃ per minute, and 8 minutes are needed; the temperature of a sample inlet is 200 ℃; the temperature of the detector is 250 ℃; the equilibrium temperature of the headspace bottle is 110 ℃, and the equilibrium time is 30 minutes; taking a reference substance solution for headspace sample injection, and recording a chromatogram map, wherein the separation degree of acetonitrile and dichloromethane is not less than 1.5; respectively taking a reference substance solution and a test sample solution for headspace sampling, recording chromatograms, and calculating peak areas according to an external standard method, wherein ethanol and ethyl acetate can not exceed 0.5%, methanol can not exceed 0.3%, N, N-dimethylformamide can not exceed 0.088%, tetrahydrofuran can not exceed 0.072%, dichloromethane can not exceed 0.06%, acetonitrile can not exceed 0.041%, N-hexane can not exceed 0.029%, and benzene can not exceed 0.0002%.
Furthermore, in the step D, 0.5g of fubitasvir is taken for burning, the value of residue left is recorded, and the residue left under the burning residue item is taken for carrying out examination according to law, so that the heavy metal content is not more than ten parts per million.
Further, in the step E, 1.0g of fubitasvir is taken into a crucible, precisely weighed, slowly burned until complete carbonization, and cooled; adding 0.5-1.0mL of nitric acid to moisten, heating at low temperature until the nitric acid vapor is removed, burning at 550-650 ℃ to completely incinerate, cooling, adding a quantitative dilute nitric acid solution for slight heating to dissolve, and taking the solution to measure the Pd content, wherein the Pd content is not more than ten parts per million.
Further, in the step F, 0.5g of forbizivir and 40mL of glacial acetic acid are precisely weighed, titrated to the first equivalent point by using perchloric acid titration solution with the concentration of 0.1mol/L, and the titration result is corrected by blank test, wherein each 1mL of perchloric acid titration solution is equivalent to 77.99mg of C 43 H 53 N 7 O 7 。
The invention has the technical effects that: compared with the prior art, the fubitasvir is not collected in China pharmacopoeia and the public new drug transfer standard 1-76 book, nor in European pharmacopoeia, united states pharmacopoeia and various pharmacopoeia forum drafts thereof; according to the registration classification of chemicals, the product is a medicament which is not sold in the market at home and abroad, and is prepared by a synthetic or semisynthetic method as a raw material medicament and a preparation thereof, so the registration classification is 1.1; according to the structure of the compound, the characteristic structures are furan rings and pyrrole rings, so that the syllables are taken as the 'Foster ratio'. The compound is a me-to medicine developed according to DACLATASIVR of the BaiSHI precious company, so that the following syllables adopt TASVIR (Virgivir), and the combined Chinese general name is forbizivir and the English general name is Fopitasvir; .
Detailed Description
To further illustrate the present invention, some embodiments are described below, which are combined with specific operation procedures to describe some implementation methods of the present invention.
Example 1
The invention provides fubitasvir, the molecular formula of which is C 43 H 53 N 7 O 7 Molecular weight of 779.92, and name 4- {2- (S) - [ N- ((S) -2-methoxycarbonylamino-3-methylbutyryl) pyrrolidine-2-yl]-1H-imidazol-5-yl } -4' - {4- [ (S) -N- ((S) -2-methoxycarbonylamino-3-methylbutanoyl) pyrrolidin-2-yl]-1H-pyrrolo [3,4-c]Tetrahydrofuran-2-yl } -1,1' -biphenyl, the molecular structural formula of which is shown in I, and the powder of which contains C calculated as anhydride 43 H 53 N 7 O 7 Not less than 97.5%;
example 2
The method for detecting the forbizir comprises the following steps of:
A. detecting impurities by high performance liquid chromatography;
chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler, a 10mmol/L potassium dihydrogen phosphate solution (1.36 g of potassium dihydrogen phosphate is taken, water is added for dissolution and dilution to 1000mL, the pH value is adjusted to 3.0 by phosphoric acid, shaking is carried out uniformly) is used as a mobile phase A, acetonitrile is used as a mobile phase B, linear gradient elution is carried out according to the table 1, the column temperature is 40 ℃, the flow rate is 1mL per minute, and the detection wavelength is 210nm; precisely weighing the fosetyl-pivoxil, adding methanol for dissolving, quantitatively diluting to prepare a solution containing 0.6mg per 1mL, taking 10 mu L of the test solution as a test solution, injecting into a liquid chromatograph, recording a chromatogram, wherein the theoretical plate number is not less than 3000 according to the main peak of the fosetyl-pivoxil, and the tailing factor is not more than 2.0. TABLE 1 Linear gradient elution Table
B. Performing isomer detection by high performance liquid chromatography;
chromatographic conditions are as follows: polysaccharide derivative is used as a filling agent; with methyl tert-butyl ether-methanol-diethylamine (500; the column temperature is 40 ℃, the flow rate is 0.5mL per minute, the detection wavelength is 340nm, an impurity E reference substance, an impurity F reference substance and a fubitasvir reference substance are respectively taken and precisely weighed, a mobile phase is added for dissolving and quantitatively diluting to prepare a solution containing 1 mu g of the impurity E and the impurity F and 0.2mg of the fubitasvir in each 1mL, the solution is taken as a system applicability solution, 20 mu L of the solution is injected into a liquid chromatograph, a chromatogram is recorded, and the separation degree between a main peak and a known adjacent peak is not less than 1.5; precisely weighing the fosbizivir, adding a mobile phase for dissolving, quantitatively diluting to prepare a solution containing 0.2mg of fosbivir in each 1mL of the solution to be used as a test solution, taking 20 mu L of the test solution, injecting the test solution into a liquid chromatograph, recording a chromatogram, and calculating the content of each impurity according to an area normalization method, wherein the peak areas of the impurities E and F are not more than 5 times (0.5%) of the main peak area.
C. Detecting the residual solvent;
the residual solvent is methanol, ethanol, acetonitrile, dichloromethane, N-hexane, ethyl acetate, tetrahydrofuran, N-dimethylformamide and benzene; precisely weighing 0.2g of fubitawei, placing the fubitawei in a headspace bottle, precisely adding 2mL of dimethyl sulfoxide, sealing the headspace bottle, and placing the headspace bottle in hot water to enable the solution in the headspace bottle to be a clear and transparent liquid to be used as a test solution; accurately weighing appropriate amounts of methanol, ethanol, acetonitrile, dichloromethane, N-hexane, ethyl acetate, tetrahydrofuran, N-dimethylformamide and benzene, adding dimethyl sulfoxide for quantitative dilution to prepare a mixed solution containing 0.3mg of methanol, 0.5mg of ethanol, 41 mu g of acetonitrile, 60 mu g of dichloromethane, 29 mu g of N-hexane, 0.5mg of ethyl acetate, 72 mu g of tetrahydrofuran, 88 mu g of N, N-dimethylformamide and 0.2 mu g of benzene in each 1mL of solution, accurately weighing 2mL of solution, placing the solution in a headspace bottle, sealing and using the solution as a reference solution; measuring according to the residual solvent measuring method, and taking a capillary column taking 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary liquid as a chromatographic column; the initial temperature is 50 ℃, the temperature is kept for 12min, and then the temperature is increased to 120 ℃ at the rate of 40 ℃ per minute, and 8 minutes are needed; the temperature of a sample inlet is 200 ℃; the temperature of the detector is 250 ℃; the equilibrium temperature of the headspace bottle is 110 ℃, and the equilibrium time is 30 minutes; taking headspace sample injection of a reference substance solution, recording a chromatogram, wherein the separation degree of acetonitrile and dichloromethane is not less than 1.5; respectively taking a reference substance solution and a test sample solution for headspace sampling, recording chromatograms, and calculating peak areas according to an external standard method, wherein ethanol and ethyl acetate can not exceed 0.5%, methanol can not exceed 0.3%, N, N-dimethylformamide can not exceed 0.088%, tetrahydrofuran can not exceed 0.072%, dichloromethane can not exceed 0.06%, acetonitrile can not exceed 0.041%, N-hexane can not exceed 0.029%, and benzene can not exceed 0.0002%.
D. Detecting firing residues and heavy metals;
0.5g of fubitasvir is burnt according to the specification of the appendix VIII N in the second part of Chinese pharmacopoeia, the value of the residue left is recorded, the residue left under the item of the burnt residue is checked according to the second method of the appendix VIII H in the second part of Chinese pharmacopoeia, and the heavy metal content cannot exceed ten parts per million.
E. Performing palladium verification; taking 1.0g of fubitasvir into a crucible, precisely weighing, slowly burning until complete carbonization, and cooling; adding 0.5-1.0mL of nitric acid to moisten, heating at low temperature until nitric acid steam is removed, burning at 550-650 ℃ to completely incinerate, cooling, adding a quantitative dilute nitric acid solution for slight heating dissolution, and taking the solution to determine the Pd content according to general rules of inductively coupled plasma atomic emission spectrometry (JY/T015-1996), wherein the Pd content is not more than ten parts per million.
F. Pair C by potentiometric titration 43 H 53 N 7 O 7 Measuring the content; precisely weighing 0.5g of fubitasvir, measuring according to a potentiometric titration method (appendix VII A of second part of Chinese pharmacopoeia), adding 40mL of glacial acetic acid, titrating to a first equivalence point by using perchloric acid titration solution with the concentration of 0.1mol/L, and correcting the titration result by using a blank test, wherein each 1mL of perchloric acid titration solution is equivalent to 77.99mg of C 43 H 53 N 7 O 7 。
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious changes and modifications as fall within the spirit of the invention are deemed to be within the scope of the invention.
Claims (5)
1. A method for detecting forbitasvir, wherein the molecular formula of the forbitasvir is C 43 H 53 N 7 O 7 Molecular weight of 779.92, and name 4- {2- (S) - [ N- ((S) -2-methoxycarbonylamino-3-methylbutyryl) pyrrolidine-2-yl]-1H-imidazol-5-yl } -4' - {4- [ (S) -N- ((S) -2-methoxycarbonylamino-3-methylbutanoyl) pyrrolidin-2-yl]-1H-pyrrolo [3,4-c]Tetrahydrofuran-2-yl } -1,1' -biphenyl, the molecular structural formula of which is shown in I, and the powder of which contains C calculated as anhydride 43 H 53 N 7 O 7 Not less than 97.5%;
（I）；
the method for detecting the fubitasvir is characterized by comprising the following steps of:
A. detecting impurities by adopting a high performance liquid chromatography;
B. performing isomer detection by high performance liquid chromatography;
C. detecting the residual solvent;
D. detecting firing residues and heavy metals;
E. performing palladium verification;
F. pair C by potentiometric titration 43 H 53 N 7 O 7 Measuring the content;
in the step A, chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent, a 10mmol/L potassium dihydrogen phosphate solution is used as a mobile phase A, and the preparation of the mobile phase A comprises the following steps: taking 1.36g of monopotassium phosphate, adding water to dissolve and dilute to 1000mL, adjusting the pH value to 3.0 by using phosphoric acid, and shaking up; taking acetonitrile as a mobile phase B, and performing linear gradient elution, wherein the column temperature is 40 ℃, the flow rate is 1 mL/min, and the detection wavelength is 210nm; precisely weighing the fosetyl-tasvir, adding methanol for dissolving, quantitatively diluting to prepare a solution containing 0.6mg in each 1mL of the solution as a test solution, taking 10 mu L of the test solution, injecting the test solution into a liquid chromatograph, recording a chromatogram, wherein the number of theoretical plates is not less than 3000 according to the main peak of the fosetyl-tasvir, and a tailing factor is not more than 2.0;
the linear gradient elutes as follows:
2. the assay method for forbizir according to claim 1, wherein in the step C, the residual solvent is methanol, ethanol, acetonitrile, dichloromethane, N-hexane, ethyl acetate, tetrahydrofuran, N-dimethylformamide and benzene.
3. The certification method of forbizir according to claim 1, wherein in the step D, 0.5g of forbizir is taken for incandescence, the value of residue left is recorded, and the residue left under the incandescence residue is taken for examination according to law, and the heavy metal content is not more than ten parts per million.
4. The method for assaying fubitasvir according to claim 1, wherein in the step E, 1.0g of fubitasvir is taken into a crucible, precisely weighed, slowly burned to be completely carbonized, and cooled; adding 0.5-1.0mL of nitric acid to moisten, heating at low temperature until the nitric acid vapor is removed, burning at 550-650 ℃ to completely incinerate, cooling, adding a quantitative dilute nitric acid solution for slight heating to dissolve, and taking the solution to measure the Pd content, wherein the Pd content is not more than ten parts per million.
5. The method for assaying forbitasvir according to claim 1, wherein in the step F, 0.5g of forbitasvir is precisely weighed, 40mL of glacial acetic acid is added, titration is performed to a first equivalence point with perchloric acid titration solution with a concentration of 0.1mol/L, and the titration result is corrected by a blank test, and each 1mL of perchloric acid titration solution corresponds to 77.99mg of C 43 H 53 N 7 O 7 。
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| CN115286639B (en) | 2023-09-22 |
| CN112461971A (en) | 2021-03-09 |
| CN115286639A (en) | 2022-11-04 |
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