Voriconazole structure identification method based on multi-dimensional nuclear magnetic resonance

Abstract

The invention relates to the technical field of voriconazole detection, in particular to a voriconazole structure identification method based on multi-dimensional nuclear magnetic resonance, and the voriconazole structure is analyzed through ultraviolet absorption spectrum (UV), infrared absorption spectrum (IR), ultrahigh resolution mass spectrum (FT-MS), 1D / 2D nuclear magnetic resonance (NMR), thermal analysis (TGA, DSC) and X-ray powder diffraction (XRD). According to the method, information of a nuclear magnetic HMBC spectrum is fully utilized, the configuration of a sample is reasonably analyzed, the result is consistent with the chemical structure of the sample, each spectrum is reasonable in attribution, the crystallinity of the voriconazole is verified through X-ray powder diffraction, the melting point and the thermal stability of the voriconazole are represented through thermal analysis, the voriconazole is detected through multiple dimensions, detection is more comprehensive, and the method is suitable for large-scale popularization and application. And accurate data support can be provided, in order to fully utilize information of the nuclear magnetic HMBC spectrum, the configuration of the sample is reasonably analyzed, the result is consistent with the chemical structure of the sample, the crystallinity of the sample is verified by X-ray powder diffraction, and the melting point and the thermal stability of the sample are represented by thermal analysis.

Description

Technical Field

[0001] The invention relates to the technical field of voriconazole detection, and in particular to a voriconazole structure identification method based on multi-dimensional nuclear magnetic resonance. Background Art

[0002] Voriconazole is a fluconazole derivative, which is mainly used clinically to treat acute or chronic deep fungal infections. It is very popular in the domestic and foreign markets and has high commercial value due to its strong antibacterial efficacy, broad antibacterial spectrum and good safety. Voriconazole has large individual differences, and therapeutic drug monitoring (TDM) is required to ensure the safety and effectiveness of the clinical application of voriconazole.

[0003] The current detection method for voriconazole is as follows: (1) Take a sample, dissolve it in ethanol and dilute it to make a solution containing about 0.2 mg per 1 mL, and measure it according to the ultraviolet-visible spectrophotometry (Appendix IVA of Part II of the 2010 edition of the Pharmacopoeia). The maximum absorption is at wavelengths of 261 nm and 267 nm, and the minimum absorption is at a wavelength of 264 nm; (2) The infrared absorption spectrum of the sample should be consistent with the reference spectrum (Figure 893 of the "Drug Infrared Spectrum Collection"); (3) The sample shows an identification reaction of organic fluoride (Appendix III of Part II of the 2010 edition of the Pharmacopoeia). However, these detection methods are not comprehensive enough and cannot provide accurate data support.

[0004] Therefore, in order to address the above-mentioned problem of being incomplete and unable to provide accurate data support, a method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance can be designed. Summary of the invention

[0005] In order to overcome the problem of incompleteness and inability to provide accurate data support.

[0006] The technical scheme of the present invention is: a method for identifying the structure of voriconazole based on multidimensional nuclear magnetic resonance, wherein the structure of voriconazole is analyzed by ultraviolet absorption spectroscopy (UV), infrared absorption spectroscopy (IR), ultra-high resolution mass spectrometry (FT-MS), 1D / 2D nuclear magnetic resonance (NMR), thermal analysis (TGA, DSC) and X-ray powder diffraction (XRD), and it is confirmed that the chemical structure of voriconazole is (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and its structural formula is as follows:

[0007]

[0008] As a preference, the method comprises the following steps:

[0009] S1: Take a voriconazole sample and dissolve it in ethanol to dilute it to obtain a diluted solution, place it in a UV-visible spectrophotometer, and measure the UV absorption spectrum of the solution;

[0010] S2: Take a voriconazole sample, use potassium bromide tabletting method to make a tablet of the sample, place it in an infrared spectrometer, and measure the infrared spectrum of the sample;

[0011] S3: Take a voriconazole sample and dissolve it in methanol: 1% formic acid aqueous solution. After filtering with a micron filter membrane, it is directly placed inside the transformation mass spectrometer and analyzed by FT-MS using the ESI positive ion mode to obtain a high-resolution mass spectrum;

[0012] S4: Take a voriconazole sample, use deuterated dimethyl sulfoxide as solvent, use a 5 mm diameter NMR sample tube, dissolve the sample in the solvent, place it in a nuclear magnetic resonance spectrometer, use TMS as the internal standard, and use a BBO broadband 5 mm probe. 1 H NMR, 13 C NMR and 19 The working frequencies of FNMR are 600.25MHz, 150.81MHz and 564.80MHz respectively. The 1D NMR test 1H-NMR spectrum width is 12019.23Hz, 13C-NMR spectrum width is 36057.69Hz, 19F-NMR spectrum width is 133 928.58Hz. The 2D NMR test includes 1 H-1HCOSY, 13 C-1H HSQC and 13 C-1H HMBC. 1 H- 1 H COSY F2( 1 H) and F1( 1 The H) dimension spectrum width is 4 807.69 Hz, and the sampling data matrix is ​​t2×t1=2 048×256; 13C- 1 H HSQC F2( 1 H) and F1( 13 C) spectral widths are 4807.69 Hz and 24 906.43 Hz respectively, 13 C- 1 H HMBC F2( 1 H) and F1( 13 The C)-dimensional spectrum widths are 4 807.69 Hz and 33524.82 Hz respectively, and the sampling data points are all t2×t1=2048×256. 1 H-NMR spectrum, deuterium exchange spectrum, 13 C-NMR spectrum, DEPT135 spectrum, DEPT90 spectrum, 19 F-NMR spectrum, 1H- 1 HCOSY spectrum, 13 C- 1 H HSQC spectrum, 13 C-1H HMBC and 1 H- 1 H NOESY;

[0013] S5: Take a voriconazole sample in an Al2O3 crucible and place it inside a thermogravimetric analyzer to analyze the melting point of the sample;

[0014] S6: Take a voriconazole sample, place it in a glass groove, flatten the surface and place it on the sample table of the X-ray diffractometer, and scan with a PIXCEL detector from 3° to 60° with a step width angle of 0.013° to obtain a spectrum.

[0015] Preferably, the UV-visible spectrophotometer in S1 is a Lambda35 UV-visible spectrophotometer; the infrared spectrometer in S2 is a VERTEX70 Fourier transform infrared spectrometer; the transform mass spectrometer in S3 is a Solarix7.0 ultra-high resolution quadrupole tandem Fourier transform mass spectrometer; the nuclear magnetic resonance spectrometer in S4 is an Ascend TM 600M superconducting nuclear magnetic resonance spectrometer; the thermogravimetric analyzer in S5 is Pyris1 TGA thermogravimetric analyzer, and its test items include:

[0016] (1) Thermogravimetric analysis (TGA): In a nitrogen atmosphere, the temperature was increased from 30°C to 500°C at 5°C / min;

[0017] (2) Differential thermal analysis (DSC): In a nitrogen atmosphere, with an empty Al dish as a reference, the temperature was raised from 30°C to 200°C at a rate of 5°C / min.

[0018] Preferably, the concentration of the diluted solution in S1 is 25 μg / ml.

[0019] Preferably, the step of using potassium bromide tabletting method to make the sample into tablets in S2 is:

[0020] (1) Prepare KBr and grinding tools. KBr should be analytical grade or spectral grade. Clean and dry the grinding tools.

[0021] (2) Grind KBr and sieve it through a 200-mesh sieve, and then dry the KBr powder;

[0022] (3) Mix the sample to be tested and KBr powder evenly, with the ratio of sample to KBr powder being 1:100;

[0023] (4) The mixture in (3) is placed in a tabletting mold and a pressure of 12 to 25 MPa is applied to form a transparent thin sheet. The tabletting time is 1±0.1 minutes to form a tablet.

[0024] Preferably, the preparation steps of methanol: 1% formic acid aqueous solution in S3 are: methanol and 1% formic acid aqueous solution are mixed and shaken at a dosage ratio of 100:1 to fully dissolve the formic acid to obtain methanol: 1% formic acid aqueous solution; the concentration of the voriconazole sample after dissolution is 0.5-5 mg / ml.

[0025] Preferably, the concentration of the solution of voriconazole dissolved in deuterated dimethyl sulfoxide in S4 is 0.5 to 5.5 mg / ml.

[0026] Preferably, the selected voriconazole sample is analyzed by liquid chromatography and its purity is greater than 99%.

[0027] The beneficial effects of the present invention are as follows: voriconazole is detected in multiple dimensions, the detection is more comprehensive, and accurate data support can be provided. In order to make full use of the information of the nuclear magnetic HMBC spectrum, the configuration of the sample is reasonably analyzed, the result is consistent with its chemical structure, the attribution of each spectrum is reasonable, the X-ray powder diffraction confirms its crystallinity, and the thermal analysis characterizes its melting point and thermal stability. The method has much lower requirements on samples than single crystal detection, and is more suitable for use in daily quality control management. The identification method of the present invention provides an analytical method and an objective basis for the qualitative study of this type of compound, which is beneficial to the quality control of the product. The structure and spectral data of the voriconazole sample are comprehensively and detailedly analyzed, providing a more convenient reference basis for the quality research of voriconazole, and also providing application examples for various spectral methods in structural identification. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 What is shown is the IR graph of voriconazole in the voriconazole structure identification method based on multidimensional nuclear magnetic resonance of the present invention;

[0029] Figure 2 What is shown is the UV-visible spectrum of voriconazole in the voriconazole structure identification method based on multi-dimensional nuclear magnetic resonance of the present invention;

[0030] Figure 3 What is shown is the FT-MS graph of voriconazole in the voriconazole structure identification method based on multidimensional nuclear magnetic resonance of the present invention;

[0031] Figure 4 What is shown is the secondary mass spectrum of voriconazole in the voriconazole structure identification method based on multidimensional nuclear magnetic resonance of the present invention;

[0032] Figure 5 The present invention shows the structure of voriconazole in the method for identifying voriconazole structure based on multidimensional nuclear magnetic resonance. 1 H-NMR spectrum;

[0033] Figure 6What is shown is the deuterium exchange spectrum of voriconazole in the voriconazole structure identification method based on multidimensional nuclear magnetic resonance of the present invention;

[0034] Figure 7 The present invention shows the structure of voriconazole in the method for identifying voriconazole structure based on multidimensional nuclear magnetic resonance. 13 C-NMR spectrum;

[0035] Figure 8 What is shown is the DEPT135 spectrum of voriconazole in the voriconazole structure identification method based on multidimensional nuclear magnetic resonance of the present invention;

[0036] Fig. 9 What is shown is the DEPT90 spectrum of voriconazole in the voriconazole structure identification method based on multidimensional nuclear magnetic resonance of the present invention;

[0037] Fig.10 The present invention shows the structure of voriconazole in the method for identifying voriconazole structure based on multidimensional nuclear magnetic resonance. 19 F-NMR spectrum;

[0038] Fig.11 Shown are TGA and DSC graphs of voriconazole in the voriconazole structure identification method based on multidimensional nuclear magnetic resonance of the present invention;

[0039] Fig.12 What is shown is the X-ray diffraction pattern of voriconazole in the voriconazole structure identification method based on multi-dimensional nuclear magnetic resonance of the present invention;

[0040] Fig.13 The present invention shows the structure of voriconazole in the method for identifying voriconazole structure based on multidimensional nuclear magnetic resonance. 1 H- 1 H COSY spectrum;

[0041] Fig.14 The present invention shows the structure of voriconazole in the method for identifying voriconazole structure based on multidimensional nuclear magnetic resonance. 13 C- 1 H HSQC spectrum;

[0042] Fig.15 The present invention shows the structure of voriconazole in the method for identifying voriconazole structure based on multidimensional nuclear magnetic resonance. 13 C- 1 H HMBC spectrum;

[0043] Fig.16 What is shown is the H-HNOESY spectrum of voriconazole in the voriconazole structure identification method based on multidimensional nuclear magnetic resonance of the present invention;

[0044] Fig.17Shown is a mass spectrum analysis diagram of voriconazole in the voriconazole structure identification method based on multi-dimensional nuclear magnetic resonance of the present invention. DETAILED DESCRIPTION

[0045] The present invention will be further described below in conjunction with the accompanying drawings and embodiments.

[0046] See also Figure 1-Figure 17 The present invention provides an embodiment: a method for identifying the structure of voriconazole based on multidimensional nuclear magnetic resonance, wherein the structure of voriconazole is analyzed by ultraviolet absorption spectroscopy (UV), infrared absorption spectroscopy (IR), ultra-high resolution mass spectrometry (FT-MS), 1D / 2D nuclear magnetic resonance (NMR), thermal analysis (TGA, DSC) and X-ray powder diffraction (XRD), comprising the following steps:

[0047] Take a voriconazole sample and dissolve it in ethanol to dilute it to prepare a diluted solution, place it inside a Lambda35 UV-visible spectrophotometer, and measure the UV absorption spectrum of the solution, such as Figure 1 As shown, the compound has an absorption peak and shoulder peak at 256 nm, which is the B band absorption of the benzene ring and heterocyclic ring, consistent with the structure of voriconazole;

[0048] Take a voriconazole sample, use potassium bromide tableting method to make a tablet, place it in the VERTEX70 Fourier transform infrared spectrometer, and measure the infrared spectrum of the sample, such as Figure 1 As shown, the compound has hydroxyl, secondary amine, 1,2,4-substituted benzene ring, methyl, methylene, ether, carbon sulfur, fluorinated benzene ring and other groups, which are consistent with the structure of voriconazole. According to the book Practical Infrared Spectrum Analysis (Lu Yongquan, Deng Zhenhua, 1989), the peak positions are assigned. The specific infrared data and analysis are shown in Table 1;

[0049] Take a voriconazole sample and dissolve it in methanol: 1% formic acid aqueous solution. After filtering with a micron filter membrane, it was directly placed inside the Solarix7.0 ultra-high resolution quadrupole tandem Fourier transform mass spectrometer, and FT-MS analysis was performed using the ESI positive ion mode to measure the high-resolution mass spectrum;

[0050] The first-level mass spectrum is shown in Figure 3 From the primary mass spectrum, it can be inferred that the quasi-molecular ion peak [M+H]+ is 350.1220. The molecular formula of m / z 350.1220 simulated by software is C 16 H 16 F3N 5O , which is consistent with the theoretical molecular formula of voriconazole;

[0051] From the secondary mass spectrum of m / z 350.1221 ( Figure 4) It can be inferred that: the sample molecule (M) obtains H+ to obtain the quasi-molecular ion peak [M+H]+ (A), A loses C2H3N3 to obtain a fragment of m / z 281.09 (B), and A loses C6H7FN2 to obtain a fragment of m / z 224.06 (C);

[0052] From the secondary mass spectrum of m / z 521.1783 ( Figure 4 ): The sample molecule (M) loses H+ to obtain the quasi-molecular ion peak [MH]- (A), and A loses C7H12O4 to obtain a fragment with m / z 361.11 (B), which is consistent with the molecular structure characteristics of voriconazole. The analysis is as follows Fig.17 ;

[0053] Take a voriconazole sample, use deuterated dimethyl sulfoxide as solvent, use a 5 mm diameter NMR sample tube, dissolve the sample in the solvent, and use Ascend TM In the 600M superconducting NMR spectrometer, TMS was used as the internal standard and the BBO broadband 5mm probe was used. 1 H NMR, 13 CNMR and 19 The working frequencies of F NMR are 600.25MHz, 150.81MHz and 564.80MHz respectively. The 1D NMR test has a 1H-NMR spectrum width of 12 019.23Hz, a 13C-NMR spectrum width of 36 057.69Hz, and a 19F-NMR spectrum width of 133 928.58Hz. The 2D NMR test includes 1 H-1H COSY, 13 C-1H HSQC and 13 C-1H HMBC. 1 H- 1 H COSY F2( 1 H) and F1( 1 The H) dimension spectrum width is 4807.69 Hz, and the sampling data matrix is ​​t2×t1=2 048×256; 13C- 1 H HSQC F2( 1 H) and F1( 13 C) spectral widths are 4 807.69 Hz and 24 906.43 Hz respectively, 13 C- 1 H HMBC F2( 1 H) and F1( 13 The C)-dimensional spectrum widths are 4 807.69 Hz and 33 524.82 Hz respectively, and the sampling data points are all t2×t1=2048×256. 1 H-NMR spectrum, deuterium exchange spectrum, 13 C-NMR spectrum, DEPT135 spectrum, DEPT90 spectrum,19 F-NMR spectrum, 1 H- 1 H COSY spectrum, 13 C- 1 H HSQC spectrum, 13 C-1H HMBC and 1 H- 1 HNOESY, such as Figure 5-10 and Figure 13-16 ;

[0054] Voriconazole 1 H-NMR spectrum ( Figure 5 )、Deuterium Exchange Spectrum( Figure 6 ), 13 C-NMR spectrum ( Figure 7 )、DEPT135 spectrum( Figure 8 )、DEPT90 spectrum( Fig. 9 ), 19 F-NMR spectrum ( Fig.10 ), 1 H- 1 H COSY spectrum ( Fig.13 ), 13 C- 1 H HSQC spectrum ( Fig.14 ), 13 C-1HHMBC( Fig.15 )and 1 H- 1 H NOESY Fig.16 ) attributed voriconazole H, C, and F, and the results are shown in Tables 2 and 3;

[0055] From the NOESY spectrum ( Fig.16 ) It can be seen that: C16-H and -OH have spatially correlated signals, indicating that the spatial configuration of C16-H and -OH belongs to the same side of the plane;

[0056] There are 14 protons in the structure of voriconazole. 1 In the H spectrum, 12 groups of peaks are given, and the integration ratio from high field to low field is 3:1:1:1:1:1:1:1:1:1:1:1:1. The total number of protons is 14, which is consistent with the compound. The chemical shift δ2.50 is the DMSO solvent peak, δ H 3.30 is the water peak in the solvent, chemical shift δ H The peak of 6.022 (1H, S) disappears after heavy water exchange. This hydrogen is active hydrogen, namely hydroxyl hydrogen. The hydroxyl group is connected to C7. H 3.58ppm is the water peak introduced by deuterium exchange;

[0057] 13 In the C spectrum, the chemical shift δ H40.0 is the DMSO solvent peak. From the structural formula of voriconazole, theoretically, there should be 1 primary carbon, 1 secondary carbon, 8 tertiary carbons, and 6 quaternary carbons. From the actual measured C spectrum, DEPT135 spectrum, and DEPT90 spectrum, the number of quaternary carbons and tertiary carbons is much more than the theoretical value. This is due to the substituted benzene ring. 19 F splits carbon. Enlarge the C spectrum and DEPT spectrum. The peak of C11 overlaps with the solvent peak. The δ C The peak at 39.95 is determined to be C11, tertiary carbon; the δ C The inverted peak at 55.86 is identified as C8, secondary carbon, corresponding to δ H 4.835(1H,D) and δ H 4.870(1H,D);δ C The positive peak at 14.26 is identified as C16, primary carbon, corresponding to δ H 1.136 (3H, D), which appears in both DEPT135 and DEPT90 C The peak at 77.35 is quaternary carbon C7;

[0058] The above substituted benzene ring 19 The splitting technique of F on carbon is published in the third edition of Spectral Analysis of Organic Compounds (note by Wu Lijun), and will not be described in detail here;

[0059] 1 In the H spectrum, δ H 1.136 (3H, D) is methyl hydrogen, the corresponding methyl primary carbon is C16, and the δ H 1.136(3H, D) and δ H 3.964 (1H, S) correlation, corresponding to the tertiary carbon is C11;

[0060] From the COSY spectrum ( Fig.13 ), δ H 6.939(1H,D) and δ H 7.3066 (1H, DD), δH7.198 (1H, DD), and δ H 7.3066(1H,DD),δ H 7.198 (1H, DD) is not related. According to the characteristics of chemical shift, it is speculated that these three H are H on the benzene ring, located in the ortho-para position. According to the HSQC spectrum ( Fig.14 ), δ H 6.939(1H,D),δ H 7.3066(1H,DD),δ H 7.198 (1H, DD) and δ C 130.91, δ C 110.30, δ C104.37 correlation, attributed to C1, C2 and C4, observe the HMBC spectrum ( Fig.15 ), δ C 162.32, δ C 159.12, δ C 124.90 is related to C1-H, C2-H, and C4-H, so it is inferred that they are in the same benzene ring. According to HSQC, the three carbons are quaternary carbons. 13 C spectrum C 162.32 and δ C δ C 159.12 is the DD peak, through the coupling constant 1 J C-F =246.0Hz, 3 J C-F =12.1Hz Analysis shows that it is quaternary carbon δ C 162.32 and δ C 159.12 by two 19 The DD peaks are caused by the splitting of F atoms, so the two groups of quaternary carbon peaks are respectively assigned to 19 F is directly connected to the quaternary carbon, while C1, C2 and C4 are affected by the quaternary carbon δ C 162.32 has a greater impact, so it is inferred that the connection sequence of the benzene ring is C1-C2-δ C 162.32-C4-δ C 159.12-δ C 124.90, predicted δ C 162.32- C 4-δ C 159.12-δ C 124.90 was assigned to C3, C5, and C6, with C3 and C5 replaced by F. The correlation was reversely verified by HMBC, which was consistent with the prediction;

[0061] According to the HSQC spectrum ( Fig.14 ), δ H 8.265(1H,S),δ H 7.638 (1H, S) and δ C 145.27, δ C 150.79 is related to C9 or C10, and according to COSY, the two hydrogens are not related. Fig.15 ), δ H 8.265(1H,S) is related to C8-H and δH7.638(1H,S), while δ H 7.638 (1H, S) is not related to C8-H, which further determines δ C 145.27, δ C 150.79 were attributed to C9 and C10 respectively;

[0062] Further NOESY spectra ( Fig.16 ) It can be seen that: C16-H and -OH have spatially correlated signals, indicating that the spatial configuration of C16-H and -OH belongs to the same side of the plane;

[0063] like Fig.11 As shown in: Take the voriconazole sample in an Al2O3 crucible and place it inside the Pyris1 TGA thermogravimetric analyzer to analyze the melting point of the sample. The test items are as follows:

[0064] Thermogravimetric analysis (TGA): in nitrogen atmosphere, the temperature was increased from 30°C to 500°C at 5°C / min;

[0065] Differential thermal analysis (DSC): In a nitrogen atmosphere, with an empty Al dish as a reference, the temperature was increased from 30°C to 200°C at 5°C / min;

[0066] DSC diagram of voriconazole sample ( Fig.11 ) has an upward endothermic peak at 139.29℃. Combined with the TGA graph ( Fig.11 ) It can be seen that the sample has no obvious weight loss in this temperature range, and the sample changes from a powder state to a molten state after the heating experiment. The endothermic peak is analyzed as melting, which is consistent with the melting point of voriconazole reported in Part II of the Chinese Pharmacopoeia (2015 Edition);

[0067] like Fig.12 As shown in: Take a voriconazole sample, place it in a glass groove, flatten the surface and place it on the X'Pert3PowderX-ray diffractometer table, scan from 3° to 60° with a step width angle of 0.013° using a PIXCEL detector to obtain a spectrum. From the relevant data of the X-ray diffraction peak (see Table 4), it can be seen that the sample is in a polycrystalline diffraction peak state and crystalline material exists.

[0068] The selected voriconazole sample was analyzed by liquid chromatography, and its purity was>99%, which met the requirements of drug structure identification.

[0069] The chemical structure of voriconazole was analyzed in detail using UV, IR, FT-MS, one-dimensional and two-dimensional nuclear magnetic resonance instruments. 1 H. 13 C was attributed in detail.

[0070] Table 1 is the infrared absorption spectrum data of voriconazole, Table 2 is the nuclear magnetic resonance spectrum data of voriconazole, Table 3 is the attribution of F-NMR, and Table 4 is a list of the main peak position values ​​of X-ray diffraction of voriconazole.

[0071]

[0072]

[0073] Table 1

[0074]

[0075]

[0076] Table 2

[0077] F <![CDATA[δ F ppm]]> F peak type F number C3-F -111.747 M 1 C5-F -107.057 M 1 C15-F -134.862 S 1

[0078] Table 3

[0079]

[0080]

[0081] Table 4

[0082] The embodiments of the present invention are described in detail above with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge scope of those skilled in the art without departing from the spirit of the present invention.

Claims

1. A method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance, characterized in that: The structure of voriconazole was analyzed by ultraviolet absorption spectroscopy (UV), infrared absorption spectroscopy (IR), ultra-high resolution mass spectrometry (FT-MS), 1D / 2D nuclear magnetic resonance (NMR), thermal analysis (TGA, DSC) and X-ray powder diffraction (XRD), confirming that the chemical structure of voriconazole is (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and its structural formula is as follows:

2. The method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance according to claim 1, characterized in that: The steps include: S1: Take a voriconazole sample and dissolve it in ethanol to dilute it to obtain a diluted solution, place it in a UV-visible spectrophotometer, and measure the UV absorption spectrum of the solution; S2: Take a voriconazole sample, use potassium bromide tabletting method to make a tablet of the sample, place it in an infrared spectrometer, and measure the infrared spectrum of the sample; S3: Take a voriconazole sample and dissolve it in methanol: 1% formic acid aqueous solution. After filtering with a micron filter membrane, it is directly placed inside the transformation mass spectrometer and analyzed by FT-MS using the ESI positive ion mode to obtain a high-resolution mass spectrum; S4: Take a voriconazole sample, use deuterated dimethyl sulfoxide as solvent, use a 5 mm diameter NMR sample tube, dissolve the sample in the solvent, place it in a nuclear magnetic resonance spectrometer, use TMS as the internal standard, and use a BBO broadband 5 mm probe. 1 H NMR, 13 C NMR and 19 The working frequencies of F NMR are 600.25MHz, 150.81MHz and 564.80MHz respectively. The 1D NMR test has a 1H-NMR spectrum width of 12019.23Hz, a 13C-NMR spectrum width of 36 057.69Hz, and a 19F-NMR spectrum width of 133 928.58Hz. The 2D NMR test includes 1 H-1HCOSY, 13 C-1H HSQC and 13 C-1H HMBC. 1 H- 1 H COSY F2( 1 H) and F1( 1 The H) dimension spectrum width is 4 807.69 Hz, and the sampling data matrix is ​​t2×t1=2 048×256; 13C- 1 H HSQC F2( 1 H) and F1( 13 C) spectral widths are 4807.69 Hz and 24 906.43 Hz respectively, 13 C- 1 H HMBC F2( 1 H) and F1( 13 The C)-dimensional spectrum widths are 4 807.69 Hz and 33524.82 Hz respectively, and the sampling data points are all t2×t1=2048×256. 1 H-NMR spectrum, deuterium exchange spectrum, 13 C-NMR spectrum, DEPT135 spectrum, DEPT90 spectrum, 19 F-NMR spectrum, 1 H- 1 HCOSY spectrum, 13 C- 1 H HSQC spectrum, 13 C-1H HMBC and 1 H- 1 H NOESY; S5: Take a voriconazole sample in an Al2O3 crucible and place it inside a thermogravimetric analyzer to analyze the melting point of the sample; S6: Take a voriconazole sample, place it in a glass groove, flatten the surface and place it on the sample table of the X-ray diffractometer, and scan with a PIXCEL detector from 3° to 60° with a step width angle of 0.013° to obtain a spectrum.

3. The method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance according to claim 2, characterized in that: The UV-visible spectrophotometer in S1 is Lambda35 UV-visible spectrophotometer; the infrared spectrometer in S2 is VERTEX70 Fourier transform infrared spectrometer; the transform mass spectrometer in S3 is Solarix7.0 ultra-high resolution quadrupole tandem Fourier transform mass spectrometer; the nuclear magnetic resonance spectrometer in S4 is Ascend TM 600M superconducting nuclear magnetic resonance spectrometer; The thermogravimetric analyzer in S5 is Pyris1 TGA thermogravimetric analyzer, and its test items include: (1) Thermogravimetric analysis (TGA): In a nitrogen atmosphere, the temperature was increased from 30°C to 500°C at 5°C / min; (2) Differential thermal analysis (DSC): In a nitrogen atmosphere, with an empty Al dish as a reference, the temperature was raised from 30°C to 200°C at a rate of 5°C / min.

4. The method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance according to claim 2, characterized in that: The concentration of the diluted solution in S1 was 25 μg / ml.

5. The method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance according to claim 2, characterized in that: The steps of preparing the sample into tablets by potassium bromide tabletting method in S2 are as follows: (1) Prepare KBr and grinding tools. KBr should be analytical grade or spectral grade. Clean and dry the grinding tools. (2) Grind KBr and sieve it through a 200-mesh sieve, and then dry the KBr powder; (3) Mix the sample to be tested and KBr powder evenly, with the ratio of sample to KBr powder being 1:100; (4) The mixture in (3) is placed in a tableting mold and a pressure of 12 to 25 MPa is applied to form a transparent thin sheet. The tableting time is 1 ± 0.1 minutes to form a tablet.

6. The method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance according to claim 2, characterized in that: The preparation steps of methanol: 1% formic acid aqueous solution in S3 are as follows: methanol and 1% formic acid aqueous solution are mixed and shaken at a dosage ratio of 100:1 to fully dissolve the formic acid to obtain methanol: 1% formic acid aqueous solution; the concentration of the voriconazole sample after dissolution is 0.5-5 mg / ml.

7. The method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance according to claim 2, characterized in that: The concentration of the solution of voriconazole dissolved in deuterated dimethyl sulfoxide in S4 is 0.5 to 5.5 mg / ml.

8. The method for structural identification of voriconazole based on multidimensional nuclear magnetic resonance according to claim 2, characterized in that: The selected voriconazole sample was analyzed by liquid chromatography and its purity was>99%.

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