CN115286639B - Fubi-tavir and verification method thereof - Google Patents
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Abstract
The invention is thatRelates to a Fubi-tavir and an assay method thereof, wherein the molecular formula of the Fubi-tavir is C 43 H 53 N 7 O 7 Molecular weight 779.92, 4- {2- (S) - [ N- ((S) -2-methoxycarbonylamino-3-methylbutanoyl) pyrrolidin-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, its molecular structure is shown as I, its powder is calculated as anhydrous substance, and contains C 43 H 53 N 7 O 7 Not less than 97.5%.
Description
Technical Field
The invention relates to research of Fubi-tavir, in particular to Fubi-tavir and an assay method thereof.
Background
Fubitavir is a novel HCV NS5A inhibitor, and the main action mechanism is to inhibit the replication of HCV by inhibiting NS5A protein, thereby achieving the effect of treating chronic hepatitis C. The preparation of the Fubitavir is prepared by Suzuki coupling reaction of an organic boric acid (ester) compound and an aryl halogen compound.
The Fubi-tavir and the detection method thereof which are low in cost and easy to realize are designed, and are technical problems which are urgently needed to be solved by the technicians in the field.
Disclosure of Invention
The invention aims to solve the technical problem of providing the Fubi-tavir and the verification method thereof, which have simple process flow and low cost.
In order to solve the technical problems, the molecular formula of the Fubi-tavir provided by the invention is C 43 H 53 N 7 O 7 Molecular weight 779.92, 4- {2- (S) - [ N- ((S) -2-methoxycarbonylamino-3-methylbutanoyl) pyrrolidin-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, its molecular structure is shown as I, its powder is calculated as anhydrous substance, and contains C 43 H 53 N 7 O 7 Not less than 97.5%;
the method for detecting the fostavir comprises the following steps of:
A. high performance liquid chromatography is adopted to detect impurities;
B. performing isomer detection by high performance liquid chromatography;
C. detecting the residual solvent;
D. burning residues and detecting heavy metals;
E. a palladium assay;
F. according to the potentiometric titration method for C 43 H 53 N 7 O 7 And (5) measuring the content.
Further, in the step a, the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler, 10mmol/L potassium dihydrogen phosphate solution (1.36 g of potassium dihydrogen phosphate is taken, water is added for dissolution and dilution to 1000mL, phosphoric acid is used for regulating the pH value to 3.0, 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 foster, adding methanol for dissolving and quantitatively diluting to prepare a solution with the concentration of 0.6mg in each 1mL, taking 10 mu L of the solution as a test solution, injecting the solution into a liquid chromatograph, recording the chromatogram, and keeping the theoretical plate number at least 3000 according to foster Wei Zhufeng and keeping the tailing factor at least 2.0.
Further, in the step B, the chromatographic conditions are as follows: polysaccharide derivatives are used as filler; methyl tertiary butyl ether-methanol-diethylamine (500:500:1) is used as a mobile phase; the column temperature is 40 ℃, the flow rate is 0.5mL per minute, the detection wavelength is 340nm, the impurity E reference substance, the impurity F reference substance and the Fubi-tavir reference substance are respectively and properly weighed, the mobile phase is added for dissolution and quantitative dilution to prepare a solution containing 1 mug of impurity E and impurity F in each 1mL, and 0.2mg of Fubi-tavir is used as a system applicability solution, 20 mug is taken and 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 fosamitavir, adding a mobile phase to dissolve and quantitatively diluting to prepare a solution containing about 0.2mg per 1mL, taking 20 mu L of the solution as a test solution, injecting the solution into a liquid chromatograph, recording a chromatogram, calculating the content of each impurity according to an area normalization method, wherein the peak area of the impurity E, F is 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.
In the step C, 0.2g of Fubi tavir is precisely weighed and placed in a headspace bottle, 2mL of dimethyl sulfoxide is precisely added, the headspace bottle is sealed, and the headspace bottle is placed in hot water to enable solution in the headspace bottle to be clear and transparent, so as to be used as a sample solution; precisely weighing proper amounts of methanol, ethanol, acetonitrile, methylene dichloride, normal hexane, ethyl acetate, tetrahydrofuran, N-dimethylformamide and benzene, adding dimethyl sulfoxide, quantitatively diluting to prepare a mixed solution containing 0.3mg of methanol, 0.5mg of ethanol, 41 mug of acetonitrile, 60 mug of methylene dichloride, 29 mug of normal hexane, 0.5mg of ethyl acetate, 72 mug of tetrahydrofuran, 88 mug of N, N-dimethylformamide and 0.2 mug of benzene in each 1mL, precisely weighing 2mL, placing in a headspace bottle, and sealing to obtain a reference solution; the method comprises the steps of measuring according to a residual solvent measuring method, and taking a capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as a fixing solution 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 the time is 8 min; the temperature of the sample inlet is 200 ℃; the detector temperature was 250 ℃; the balance temperature of the headspace bottle is 110 ℃, and the balance time is 30 minutes; taking a control solution headspace for sample injection, recording a chromatogram, wherein the separation degree of acetonitrile and dichloromethane is not less than 1.5; taking a control solution and a test solution, respectively taking headspace samples, recording chromatograms, calculating according to an external standard method and peak areas, wherein the peak areas are not more than 0.5%, the peak areas are not more than 0.3% of ethanol, the peak areas are not more than 0.088% of N, N-dimethylformamide, the peak areas are not more than 0.072% of tetrahydrofuran, the peak areas are not more than 0.06% of dichloromethane, the peak areas are not more than 0.041% of acetonitrile, the peak areas are not more than 0.029% of N-hexane, and the peak areas are not more than 0.0002% of benzene.
Further, in the step D, 0.5g of Fubi tavir is taken for burning, the numerical value of the remained residue is recorded, the remained residue under the burning residue item is taken for legal inspection, and the heavy metal content is not more than ten parts per million.
In the step E, 1.0g of Fubi-tavir is taken into a crucible, precisely weighed, slowly burnt until being completely carbonized, and cooled; adding 0.5-1.0mL of nitric acid to wet, heating at low temperature until the nitric acid steam is removed, burning at 550-650 ℃ to completely ash, cooling, adding quantitative diluted nitric acid solution to slightly dissolve, taking the solution to measure Pd content, and ensuring that the Pd content is not more than ten parts per million.
Further, in the above step F, 0.5g of Fubitavir was precisely weighed, 40mL of glacial acetic acid was added, the resulting mixture was titrated to the first equivalent point with a perchloric acid titration solution having a concentration of 0.1mol/L, and the result of the titration was corrected by a blank test, wherein each 1mL of perchloric acid titration solution corresponds 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 Fubi-tavir disclosed by the invention is not received in the Chinese pharmacopoeia and the published new drug conversion standard 1-76 volumes at present, and is not received in European pharmacopoeia, united states pharmacopoeia and draft of each pharmacopoeia forum; according to the registration classification of chemical medicines, the medicine is not sold in the market at home and abroad, and raw medicines and preparations thereof prepared by a synthetic or semi-synthetic method are registered and classified as 1.1 class; according to the structure of the compound, the characteristic structure is furan ring and pyrrole ring, so syllable 'Fubi' is taken. The compound is a 'me-to' type drug developed according to DACLATASIVR of Bai-Shi-Guibao company, so that subsequent syllables adopt 'TASVIR' (tavir), and the Chinese common name is Fubi-tavir, and the English common name is Fopitasvir; .
Detailed Description
To further illustrate the invention, the following description is of specific embodiments, and describes some implementations of the invention in connection with specific procedures.
Example 1
The molecular formula of the fosratavir provided by the invention is C 43 H 53 N 7 O 7 Molecular weight 779.92, 4- {2- (S) - [ N- ((S) -2-methoxycarbonylamino-3-methylbutanoyl) pyrrolidin-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, its molecular structure is shown as I, its powder is calculated as anhydrous substance, and contains C 43 H 53 N 7 O 7 Not less than 97.5%;
example 2
The method for detecting the fostavir comprises the following steps of:
A. high performance liquid chromatography is adopted to detect impurities;
chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler, 10mmol/L potassium dihydrogen phosphate solution (1.36 g of potassium dihydrogen phosphate is taken, water is added for dissolution and dilution to 1000mL, phosphoric acid is used for regulating the pH value to 3.0, 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 foster, adding methanol for dissolving and quantitatively diluting to prepare a solution with the concentration of 0.6mg in each 1mL, taking 10 mu L of the solution as a test solution, injecting the solution into a liquid chromatograph, recording the chromatogram, and keeping the theoretical plate number at least 3000 according to foster Wei Zhufeng and keeping the tailing factor at least 2.0. TABLE 1 Linear gradient elution Table
B. Performing isomer detection by high performance liquid chromatography;
chromatographic conditions: polysaccharide derivatives are used as filler; methyl tertiary butyl ether-methanol-diethylamine (500:500:1) is used as a mobile phase; the column temperature is 40 ℃, the flow rate is 0.5mL per minute, the detection wavelength is 340nm, the impurity E reference substance, the impurity F reference substance and the Fubi-tavir reference substance are respectively and properly weighed, the mobile phase is added for dissolution and quantitative dilution to prepare a solution containing 1 mug of impurity E and impurity F in each 1mL, and 0.2mg of Fubi-tavir is used as a system applicability solution, 20 mug is taken and 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 fosamitavir, adding a mobile phase to dissolve and quantitatively diluting to prepare a solution containing about 0.2mg per 1mL, taking 20 mu L of the solution as a test solution, injecting the solution into a liquid chromatograph, recording a chromatogram, calculating the content of each impurity according to an area normalization method, wherein the peak area of the impurity E, F is not more than 5 times (0.5%) of the main peak area.
C. Detecting the residual solvent;
the residual solvent is methanol, ethanol, acetonitrile, methylene dichloride, normal hexane, ethyl acetate, tetrahydrofuran, N-dimethylformamide and benzene; precisely weighing 0.2g of Fubi tavir, placing into a headspace bottle, precisely adding 2mL of dimethyl sulfoxide, sealing the headspace bottle, and placing into hot water to make the solution in the headspace bottle become clear and transparent liquid to be used as a sample solution; precisely weighing proper amounts of methanol, ethanol, acetonitrile, methylene dichloride, normal hexane, ethyl acetate, tetrahydrofuran, N-dimethylformamide and benzene, adding dimethyl sulfoxide, quantitatively diluting to prepare a mixed solution containing 0.3mg of methanol, 0.5mg of ethanol, 41 mug of acetonitrile, 60 mug of methylene dichloride, 29 mug of normal hexane, 0.5mg of ethyl acetate, 72 mug of tetrahydrofuran, 88 mug of N, N-dimethylformamide and 0.2 mug of benzene in each 1mL, precisely weighing 2mL, placing in a headspace bottle, and sealing to obtain a reference solution; the method comprises the steps of measuring according to a residual solvent measuring method, and taking a capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as a fixing solution 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 the time is 8 min; the temperature of the sample inlet is 200 ℃; the detector temperature was 250 ℃; the balance temperature of the headspace bottle is 110 ℃, and the balance time is 30 minutes; taking a control solution headspace for sample injection, recording a chromatogram, wherein the separation degree of acetonitrile and dichloromethane is not less than 1.5; taking a control solution and a test solution, respectively taking headspace samples, recording chromatograms, calculating according to an external standard method and peak areas, wherein the peak areas are not more than 0.5%, the peak areas are not more than 0.3% of ethanol, the peak areas are not more than 0.088% of N, N-dimethylformamide, the peak areas are not more than 0.072% of tetrahydrofuran, the peak areas are not more than 0.06% of dichloromethane, the peak areas are not more than 0.041% of acetonitrile, the peak areas are not more than 0.029% of N-hexane, and the peak areas are not more than 0.0002% of benzene.
D. Burning residues and detecting heavy metals;
0.5g of Fubi tavir is burnt according to the regulations of annex VIII N of the second part of Chinese pharmacopoeia, the numerical value of the remained residue is recorded, and residues remained under the burnt residue item are checked according to the second method of annex VIII H of the second part of Chinese pharmacopoeia, wherein the heavy metal content is not more than ten parts per million.
E. A palladium assay; 1.0g of Fubi tavir is taken into a crucible, precisely weighed, slowly burnt until being completely carbonized, and cooled; adding 0.5-1.0mL of nitric acid to moisten, heating at low temperature until the nitric acid steam is completely removed, burning at 550-650 ℃ to completely ash, cooling, adding quantitative diluted nitric acid solution to slightly thermally dissolve, and taking the solution to measure Pd content according to the general rule of inductively coupled plasma atomic emission spectrometry (JY/T015-1996), wherein Pd content is not more than ten parts per million.
F. According to the potentiometric titration method for C 43 H 53 N 7 O 7 Measuring the content; 0.5g of Fubi-tavir is precisely weighed, 40mL of glacial acetic acid is added according to a potentiometric titration method (VII A of the second appendix of Chinese pharmacopoeia), the titration is carried out to a first equivalent point by using a perchloric acid titration solution with the concentration of 0.1mol/L, and the titration result is corrected 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 is apparent that the above examples are merely illustrative of the present invention and are not limiting of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. And obvious changes and modifications which come within the spirit of the invention are desired to be protected.
Claims (1)
1. Method for detecting Fubi-tavir, wherein FubiTavir has formula C 43 H 53 N 7 O 7 Molecular weight 779.92, 4- {2- (S) - [ N- ((S) -2-methoxycarbonylamino-3-methylbutanoyl) pyrrolidin-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, its molecular structure is shown as I, its powder is calculated as anhydrous substance, and contains C 43 H 53 N 7 O 7 Not less than 97.5%;
（I）；
the method for detecting the fostavir comprises the following steps of:
A. high performance liquid chromatography is adopted to detect impurities;
B. performing isomer detection by high performance liquid chromatography;
C. detecting the residual solvent;
D. burning residues and detecting heavy metals;
E. a palladium assay;
F. according to the potentiometric titration method for C 43 H 53 N 7 O 7 Measuring the content;
in the step a, the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler, 10mmol/L potassium dihydrogen phosphate solution 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 foster-tavir, adding methanol for dissolving and quantitatively diluting to prepare a solution containing 0.6mg per 1mL, taking 10 mu L of the solution as a test solution, injecting the solution into a liquid chromatograph, recording the chromatogram, and keeping the theoretical plate number of the solution to be tested at least 3000 according to foster-tavir Wei Zhufeng and keeping the tailing factor at least 2.0;
preparation of the mobile phase A: taking 1.36g of monopotassium phosphate, adding water for dissolution and dilution to 1000mL, regulating the pH value to 3.0 by using phosphoric acid, and shaking uniformly;
the linear gradient elution is as follows:
；
In the step D, 0.5g of Fubi tavir is burnt, the numerical value of the remained residues is recorded, the remained residues under the burnt residues are checked in a legal manner, and the heavy metal content is not more than ten parts per million;
in the step E, 1.0g of Fubi tavir is taken into a crucible, precisely weighed, slowly burnt until completely carbonized, and cooled; adding 0.5-1.0mL of nitric acid to wet, heating at low temperature until the nitric acid steam is removed, burning at 550-650 ℃ to completely ash, cooling, adding quantitative diluted nitric acid solution to slightly dissolve, taking the solution to measure Pd content, and ensuring that the Pd content is not more than ten parts per million.
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