CN115477642A - Voriconazole raw material medicine impurity and preparation method and application thereof - Google Patents
Voriconazole raw material medicine impurity and preparation method and application thereof Download PDFInfo
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- CN115477642A CN115477642A CN202211164855.9A CN202211164855A CN115477642A CN 115477642 A CN115477642 A CN 115477642A CN 202211164855 A CN202211164855 A CN 202211164855A CN 115477642 A CN115477642 A CN 115477642A
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- 239000012535 impurity Substances 0.000 title claims abstract description 34
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 title claims abstract description 25
- 229960004740 voriconazole Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 title abstract description 9
- 239000002994 raw material Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 238000001514 detection method Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- -1 (1H-1, 2, 4-triazole-1-yl) methyl Chemical group 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000011968 lewis acid catalyst Substances 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 238000011084 recovery Methods 0.000 description 8
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 6
- 239000004593 Epoxy Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 241000235645 Pichia kudriavzevii Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 240000004460 Tanacetum coccineum Species 0.000 description 1
- 241000222126 [Candida] glabrata Species 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 208000032343 candida glabrata infection Diseases 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 231100000734 genotoxic potential Toxicity 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229940010175 vfend Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
-
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
Abstract
The invention discloses voriconazole bulk drug impurities and a preparation method and application thereof. In the process of synthesizing the intermediate of voriconazole, the impurity introduced in the intermediate product in the previous step is subjected to cyclization reaction under the condition to obtain the impurity, the intermediate has a structure shown as a formula (I), and the voriconazole impurity has a structure shown as a formula (II).
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a novel related substance (impurity) in a voriconazole production process, a synthetic method and application thereof.
Background
Voriconazole is a broad-spectrum triazole antifungal drug developed by feverfew corporation, marketed in europe in 2002 under the name Vfend. The medicine has been marketed in dozens of countries around the world, has broad-spectrum antifungal effect, has antibacterial effect on candida (including fluconazole-resistant candida krusei, candida glabrata and candida albicans drug-resistant strains), and has antibacterial effect on all detected aspergillus fungi. In addition, voriconazole has bactericidal effects in vitro against other pathogenic fungi, including those less sensitive to existing antifungal agents, such as podophyllotobacter and fusarium.
The pfeiri patent US6586594 discloses a main stream of voriconazole synthesis route, which comprises the following steps:
in the above synthetic route, the first bromination step produces dibromo-substituted impurities, i.e., compounds represented by formula (iv), as follows:
the introduced compound (IV) and the compound (III) generate a target impurity compound shown as a formula (II) through a Leformalin-TestyReformastay coupling reaction, and the impurity has potential genotoxicity.
Disclosure of Invention
When the dibromo substituted impurity compound (IV) participates in a Reformastay reaction, a cyclization reaction can occur in the process to generate voriconazole impurities 4- (3- ((1H-1, 2, 4-triazol-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyl epoxy ethyl-2-yl) -6-chloro-5-fluoropyrimidine, and the structure of the compound is shown as the formula (II):
the invention provides a new related substance existing in a voriconazole production process, and provides an economic and simple preparation method of the related substance, and application of the related substance as a reference substance of the related substance in the voriconazole production process for controlling the quality of voriconazole.
The invention provides an impurity (or related substances) of voriconazole bulk drug, the chemical name of the impurity is as follows: 4- (3- ((1H-1, 2, 4-triazole-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyl epoxy ethyl-2-yl) -6-chloro-5-fluoropyrimidine, which has a structure shown in a formula (II):
the invention also provides a preparation method of 4- (3- ((1H-1, 2, 4-triazole-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyl epoxy ethyl-2-yl) -6-chloro-5-fluoropyrimidine, which comprises the following steps:
reacting a compound shown as a formula (IV) with a compound shown as a formula (III) in the presence of zinc, iodine and a Lewis acid catalyst to obtain a target impurity compound shown as a formula (II)
In the preparation method of the present invention, the reaction is carried out in an aprotic solvent which is a mixed solvent of one or more of tetrahydrofuran, 2-methyltetrahydrofuran and methyl t-butyl ether, preferably tetrahydrofuran.
In the preparation method of the present invention, the lewis acid is ferric chloride, zinc chloride or trimethylchlorosilane, preferably trimethylchlorosilane.
In the preparation method, the molar ratio of the compound (III) to the zinc powder, the iodine, the compound (IV) and the Lewis acid catalyst is 1: (2-6): (1-5): (1-5): (1 to 5), preferably, 1: (3-5): (1-2): (1-1.3): (1-2).
In the preparation method of the invention, the reaction temperature is-20 ℃ to 5 ℃, preferably-20 ℃ to 0 ℃.
In the preparation method of the invention, the reaction is carried out under the protection of inert gas, and the inert gas is nitrogen or helium.
In the preparation method of the invention, after the reaction is completed, the method further comprises the following recrystallization operation: and (3) recrystallizing the compound shown in the formula (II) obtained by the reaction, wherein the solvent used for recrystallization is lower alkanol, and the lower alkanol is methanol, ethanol or isopropanol, preferably isopropanol.
The invention also provides application of the 4- (3- ((1H-1, 2, 4-triazole-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyl epoxy ethyl-2-yl) -6-chloro-5-fluoropyrimidine, namely the compound shown in the formula (II) which is used as a reference substance for impurity detection in the voriconazole production process.
The invention also provides a detection method of 4- (3- ((1H-1, 2, 4-triazole-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyl epoxy ethyl-2-yl) -6-chloro-5-fluoropyrimidine, which comprises the following steps:
LC-MS instrument, liquid phase method: detecting wave of 265nm, column temperature of 50 deg.C, flow rate of 0.3ml/min, sample amount of 20ul, mobile phase of 0.1% FA water solution and pure acetonitrile, elution procedure of gradient, and running time of 25min; the mass spectrometry method comprises the following steps: dry gas flow rate 12L/min, atomizer pressure 45psi, dry gas temperature 350 deg.C, capillary voltage 3000ev, detection mode SIM, channel EST ﹢ Collision voltage 70ev;
sample treatment: the diluent is 40% acetonitrile, the concentration of the sample is 5mg/ml, and the concentration of the impurity reference substance is 18.75ng/ml;
detection limit: the limit of quantitation is 0.0056ppm, the sensitivity is 0.0056ppm, and the limit of detection is 0.0028ppm.
Linearity and range: preparing linear solution according to the limit concentration and 30%, 50%, 80%, 100% and 150% of the limit concentration, wherein the linear coefficient is more than 0.99, the corresponding percentage of the Y-axis intercept accounting for 100% is less than 25%, and the linearity meets the regulation;
accuracy: and the recovery rate is between 78.8 and 101.9 percent, the average recovery rate is 91.9 percent, the recovery rate RSD percent is 7.6 percent, and the recovery rate meets the requirement.
The invention has the beneficial effects that:
the high-purity voriconazole impurity 4- (3- ((1H-1, 2, 4-triazole-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyl epoxy ethyl-2-yl) -6-chloro-5-fluoropyrimidine, which is a compound shown in a formula (II), can be used as an impurity reference substance in voriconazole intermediate detection analysis, so that the accurate positioning and quantification of the voriconazole intermediate on the impurity in the detection are improved, the control on the impurity is favorably strengthened, and the quality of a voriconazole finished product is improved.
Drawings
FIG. 1 is an HPLC chromatogram of the impurity 4- (3- ((1H-1, 2, 4-triazol-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyloxiranyl-2-yl) -6-chloro-5-fluoropyrimidine;
FIG. 2 is a mass spectrum of 4- (3- ((1H-1, 2, 4-triazol-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyloxiranyl-2-yl) -6-chloro-5-fluoropyrimidine as an impurity;
FIG. 3 is a nuclear magnetic spectrum of 4- (3- ((1H-1, 2, 4-triazol-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methyloxiranyl-2-yl) -6-chloro-5-fluoropyrimidine as an impurity;
FIG. 4 shows the linearity and range of the detection method.
Detailed Description
In the examples of the present invention, the apparatus and conditions involved are as follows:
nuclear magnetic instrument: BRUKER 600M superconducting nuclear magnetic spectrometer
HPLC apparatus: agilent
HPLC chromatographic conditions:
and (3) chromatographic column: 4.6 x 250mm, filler: c18 (e.g., ZORBAX SB-C18), detection wavelength: 265nm, column temperature: 35 ℃, flow rate: 1.5ml/min, sample size: 50ul, mobile phase: buffer-methanol-acetonitrile =40, buffer: 0.02mol/L ammonium acetate solution (pH adjusted to 4.0 with glacial acetic acid), elution procedure: isocratic, run time: and (5) 25min.
LC-MS instrument: agilent 1260HPLC+6120MS (single four-level rod)
LC-MS conditions:
a chromatographic column: agilent 20RBAX Eclipse Plus C18,3.0 × 150mm,1.8mm;
the liquid phase method comprises the following steps: the detection wave is 265nm, the column temperature is 50 ℃, the flow rate is 0.3ml/min, and the sample injection amount is 20ul; the mobile phase is 0.1% formic acid water solution and pure acetonitrile, the elution procedure is gradient, and the running time is 25min;
the mass spectrometry method comprises the following steps: dry gas flow rate 12L/min, atomizer pressure 45psi, dry gas temperature 350 ℃, capillary voltage 3000ev, detection mode SIM, channel EST +, collision voltage 70ev.
Example 1
Adding 1.82g of zinc powder into a 100mL reaction bottle, replacing with nitrogen, then adding 7mL of tetrahydrofuran, starting magnetic stirring, cooling the system to 0-20 ℃, then adding 1.12g of trimethylchlorosilane, keeping the temperature for reaction for 15 minutes, controlling the temperature to 20-40 ℃, dropwise adding a mixed solution of 2.28g of iodine and 5mL of tetrahydrofuran, keeping the temperature for reaction for 0.5h after dropwise adding, then cooling to below-5 ℃, then controlling the temperature to 0 ℃ -20 ℃, dropwise adding a mixed solution of 2.00g of a compound (III) and 2.84g of a compound (IV) in 10mL of tetrahydrofuran, keeping the temperature for reaction for 0.5h after dropwise adding, then filtering, adjusting the pH of the system to 8-10 by using a saturated aqueous solution of sodium carbonate in ice water, filtering, extracting the filtrate by using 50mL of ethyl acetate, washing the organic phase by using saturated saline, evaporating the organic phase to dryness at 30 ℃, performing column chromatography on the residue by using ethyl acetate/n-heptane (V/V =1 light yellow 5) to obtain a white-like solid, recrystallizing by using isopropanol to obtain 555 purity: 94.3% (fig. 1), LC-MS:382.1 (M + H) + ) (fig. 2), 1HNMR (600mhz, dmso-d 6) δ 8.76 (s, 1H), 8.42 (s, 1H), 7.72 (s, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 6.62 (s, 1H), 5.47 (d, J =14.6hz, 1h), 4.90 (d, J =14.7hz, 1h), 2.28 (s, 3H) (fig. 3).
Example 2
Adding 1.82g of zinc powder into a 100mL reaction bottle, replacing with nitrogen, then adding 7mL of tetrahydrofuran, starting magnetic stirring, cooling the system to 0-20 ℃, then adding 1.22g of zinc chloride, reacting for 15 minutes under heat preservation, controlling the temperature to 20-40 ℃, dropwise adding a mixed solution of 2.29g of iodine and 5mL of tetrahydrofuran, reacting for 0.5 hour under heat preservation after dropwise adding, then cooling to below-5 ℃, then controlling the temperature to 0-20 ℃, dropwise adding a mixed solution of 2.00g of a compound (III) and 2.83g of a compound (IV) in 10mL of tetrahydrofuran, reacting for 0.5 hour under heat preservation after dropwise adding, then filtering, adjusting the pH of the system to 8-10 by using a saturated aqueous solution of sodium carbonate in ice water, filtering, extracting the filtrate by using 50mL of ethyl acetate, washing the organic phase by using saturated saline, evaporating the organic phase to dryness under reduced pressure at 30 ℃, performing column chromatography on the residue by using ethyl acetate/n-heptane (V/V =1 light yellow 5) to obtain a white-like solid, recrystallizing by using isopropanol to obtain 0.17g of purity: 96.5 percent.
Example 3
Adding 2.93g of zinc powder into a 100mL reaction bottle, replacing with nitrogen, then adding 7mL of tetrahydrofuran, starting magnetic stirring, cooling the system to 0-20 ℃, then adding 1.46g of trimethylchlorosilane, keeping the temperature for reaction for 15 minutes, controlling the temperature to 20-40 ℃, dropwise adding a mixed solution of 2.27g of iodine and 5mL of tetrahydrofuran, keeping the temperature for reaction for 0.5h after dropwise adding, then cooling to below-5 ℃, then controlling the temperature to 0-20 ℃, dropwise adding a mixed solution of 2.00g of a compound (III) and 2.87g of a compound (IV) in 10mL of tetrahydrofuran, keeping the temperature for reaction for 0.5h after dropwise adding, then filtering, adjusting the pH of the system to 8-10 by using a saturated aqueous solution of sodium carbonate in ice water, filtering, extracting the filtrate by using 50mL of ethyl acetate, washing the organic phase by using saturated saline, evaporating the organic phase to dryness at 30 ℃, performing column chromatography on the residue by using ethyl acetate/n-heptane (V/V =1 light yellow 5) to obtain a white-like solid, recrystallizing by using isopropanol to obtain 0.22g of purity: 97.2 percent.
Example 4
The compound shown in the formula (II) (namely C09-B-ZZ 13) is a potential genotoxic impurity, the limit of control in bulk drug voriconazole is 3.75ppm, and the impurity cannot be detected by the existing detection method, so the detection method of the impurity is researched, and a detection analysis method capable of qualitatively and quantitatively detecting the impurity is developed. The method comprises the following steps:
LC-MS instrument, liquid phase method: detection wave of 265nm, column temperature of 50 deg.C, flow rate of 0.3ml/min, sample amount of 20ul, mobile phase of 0.1% FA and pure acetonitrile, elution program of gradient, and running time of 25min; the mass spectrometry method comprises the following steps: dry gas flow rate 12L/min, atomizer pressure 45psi, dry gas temperature 350 deg.C, capillary voltage 3000ev, detection mode SIM, channel EST ﹢ And an impact voltage of 70ev.
Sample treatment: the diluent is 40% acetonitrile, the sample concentration is 5mg/ml, and the impurity control substance concentration is 18.75ng/ml.
Detection limit: the limit of quantitation is 0.0056ppm, the sensitivity is 0.0056ppm, and the limit of detection is 0.0028ppm.
Linearity and range: linear solutions are prepared according to the limit concentration and 30%, 50%, 80%, 100% and 150% of the limit concentration, the linear coefficient is greater than 0.99, the corresponding percentage of the Y-axis intercept accounting for 100% is less than 25%, and the linearity meets the specification (as shown in figure 4).
Accuracy: and the recovery rate is between 78.8 and 101.9 percent, the average recovery rate is 91.9 percent, the recovery rate RSD percent is 7.6 percent, and the recovery rate meets the requirement.
The content of the compound (II) in the compound (I) is 1.7ppm by the detection of the conditions, and the impurity is not found in the bulk drug voriconazole. The invention is beneficial to improving the safety of the medicine by controlling the quality of the voriconazole, such as controlling the content of the potential genotoxic impurity compound (II) not more than 3.75ppm.
Claims (10)
1. An impurity voriconazole, its chemical name is: 4- (3- ((1H-1, 2, 4-triazole-1-yl) methyl) -3- (2, 4-difluorophenyl) -2-methylepoxyethyl-2-yl) -6-chloro-5-fluoropyrimidine, which has the structure shown in the formula (II):
2. a process for preparing a compound of claim 1, comprising the steps of:
reacting a compound shown in a formula (IV) with a compound shown in a formula (III) in the presence of zinc, iodine and a Lewis acid catalyst to obtain a compound shown in an impurity formula (II);
3. the process for preparing the compound of claim 2, wherein the reaction is carried out under the protection of an inert gas, and the inert gas is nitrogen or helium.
4. The method for preparing the compound according to claim 2, wherein the reaction is carried out in an aprotic solvent, which is a mixed solvent of one or more of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether, preferably tetrahydrofuran.
5. A process for the preparation of a compound according to claim 2, wherein the lewis acid is ferric chloride, zinc chloride or trimethylchlorosilane, preferably trimethylchlorosilane.
6. A process for the preparation of the compound according to claim 2, characterized in that the compound (iii) is used in an amount of: zinc powder: iodine: compound (iv): the molar ratio of Lewis acid is 1: (2-6): (1-5): (1-5): (1 to 5), preferably, 1: (3-5): (1-2): (1-1.3): (1-2).
7. The process according to claim 2, wherein the reaction is carried out at a temperature of-20 ℃ to 5 ℃, preferably-20 ℃ to 0 ℃.
8. The method according to claim 2, wherein the reaction time is 0.2 to 1 hour.
9. The method of claim 2, wherein after said reacting, further comprising recrystallizing; the solvent used for recrystallization is lower alkanol, and the lower alkanol is methanol, ethanol or isopropanol, preferably isopropanol.
10. Use of the compound of claim 1 as a reference for the detection of impurities in voriconazole production.
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| CN115856144A (en) * | 2022-12-19 | 2023-03-28 | 华夏生生药业(北京)有限公司 | Detection method of trimethyl sulfoxide iodide impurity in fluconazole raw material medicine and injection |
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| CN108059617A (en) * | 2018-02-06 | 2018-05-22 | 成都倍特药业有限公司 | The impurity and its synthetic method of the chloro- 6- ethyls -5-FUs of voriconazole starting material 4- |
| CN110305113A (en) * | 2019-07-05 | 2019-10-08 | 镇江市第四人民医院（镇江市妇幼保健院） | A kind of synthetic method of voriconazole impurity B |
| CN112645935A (en) * | 2020-12-15 | 2021-04-13 | 植恩生物技术股份有限公司 | Preparation method of voriconazole key intermediate |
| CN114057699A (en) * | 2021-07-13 | 2022-02-18 | 陕西丽彩药业有限公司 | Preparation method of voriconazole intermediate raceme |
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| CN108059617A (en) * | 2018-02-06 | 2018-05-22 | 成都倍特药业有限公司 | The impurity and its synthetic method of the chloro- 6- ethyls -5-FUs of voriconazole starting material 4- |
| CN110305113A (en) * | 2019-07-05 | 2019-10-08 | 镇江市第四人民医院（镇江市妇幼保健院） | A kind of synthetic method of voriconazole impurity B |
| CN112645935A (en) * | 2020-12-15 | 2021-04-13 | 植恩生物技术股份有限公司 | Preparation method of voriconazole key intermediate |
| CN114057699A (en) * | 2021-07-13 | 2022-02-18 | 陕西丽彩药业有限公司 | Preparation method of voriconazole intermediate raceme |
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| CN115856144A (en) * | 2022-12-19 | 2023-03-28 | 华夏生生药业(北京)有限公司 | Detection method of trimethyl sulfoxide iodide impurity in fluconazole raw material medicine and injection |
| CN115856144B (en) * | 2022-12-19 | 2023-07-07 | 华夏生生药业(北京)有限公司 | Method for detecting trimethyl sulfoxide iodide impurity in fluconazole bulk drug and injection |
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