CN111995616A - Tedizolid phosphate impurity and preparation method and application thereof - Google Patents
Tedizolid phosphate impurity and preparation method and application thereof Download PDFInfo
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- CN111995616A CN111995616A CN202011005126.XA CN202011005126A CN111995616A CN 111995616 A CN111995616 A CN 111995616A CN 202011005126 A CN202011005126 A CN 202011005126A CN 111995616 A CN111995616 A CN 111995616A
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- 239000012535 impurity Substances 0.000 title claims abstract description 100
- 229960003947 tedizolid phosphate Drugs 0.000 title claims abstract description 71
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 38
- 239000013558 reference substance Substances 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 48
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 44
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 239000003960 organic solvent Substances 0.000 claims description 32
- 239000012071 phase Substances 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 235000019270 ammonium chloride Nutrition 0.000 claims description 22
- 229940125904 compound 1 Drugs 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 229940125782 compound 2 Drugs 0.000 claims description 16
- 229940126214 compound 3 Drugs 0.000 claims description 16
- 238000000926 separation method Methods 0.000 claims description 15
- 238000001514 detection method Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- 239000012022 methylating agents Substances 0.000 claims description 10
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 10
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 10
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 239000012085 test solution Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- 238000004262 preparative liquid chromatography Methods 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000004811 liquid chromatography Methods 0.000 claims description 2
- 239000004973 liquid crystal related substance Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000012088 reference solution Substances 0.000 claims description 2
- 238000010517 secondary reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 22
- 230000008569 process Effects 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 16
- 230000002194 synthesizing effect Effects 0.000 abstract description 7
- VOEFRGFXMMXFGK-UHFFFAOYSA-N 2-(2-methyltetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound CN1N=NC(C=2N=CC(=CC=2)B2OC(C)(C)C(C)(C)O2)=N1 VOEFRGFXMMXFGK-UHFFFAOYSA-N 0.000 abstract description 5
- 238000003908 quality control method Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 4
- 238000012544 monitoring process Methods 0.000 abstract description 4
- 238000005457 optimization Methods 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000000523 sample Substances 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- DMSHUVBQFSNBBL-UHFFFAOYSA-N 5-bromopyridine-2-carbonitrile Chemical compound BrC1=CC=C(C#N)N=C1 DMSHUVBQFSNBBL-UHFFFAOYSA-N 0.000 description 3
- 241001251200 Agelas Species 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 241000588807 Bordetella Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- NTWMKNSGFIRDSF-OAHLLOKOSA-N CN1N=NC(C(N=C2)=CC=C2C(C=CC(N(C[C@@H](OP(C)(O)=O)O2)C2=O)=C2)=C2F)=N1 Chemical compound CN1N=NC(C(N=C2)=CC=C2C(C=CC(N(C[C@@H](OP(C)(O)=O)O2)C2=O)=C2)=C2F)=N1 NTWMKNSGFIRDSF-OAHLLOKOSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 229960003879 tedizolid Drugs 0.000 description 1
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
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- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/36—Control of physical parameters of the fluid carrier in high pressure liquid systems
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
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- Spectroscopy & Molecular Physics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a tedizolid phosphate impurity, a preparation method and application thereof, and belongs to the field of chemical pharmacy. The structural formula of the impurity is shown as a formula I. The impurities are generated in the process of synthesizing 2- (2-methyl-2H-tetrazole-5-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine intermediate, and the impurities seriously affect the product quality. The invention synthesizes and separates the impurities, has the purity higher than 96 percent and conforms to the national pharmacopoeia and the Chinese pharmacopoeiaThe national drug code relates to the quality requirements of impurity reference substances. The impurity preparation process is simple and stable, the repeatability is good, the prepared impurity 2- (2-methyl-tetrazole) -5-azidopyridine can be used as a reference substance, is applied to the quality control of tedizolid phosphate API, bulk drugs and preparations, can also provide a reliable monitoring means for the process research, promotes the process optimization and determination process, and has good application prospect.
Description
Technical Field
The invention relates to a tedizolid phosphate impurity, a preparation method and application thereof, and belongs to the field of chemical pharmacy.
Background
Tedizolid phosphate is a novel oxazolidinone antibiotic developed by Cubist pharmaceutical company and has the chemical name { (5R) - (3- { 3-fluoro-4- [6- (2-methyl-2H-tetrazol-5-yl) -pyridin-3-yl ] phenyl } -2-oxooxazolidin-5-yl) } methylphosphonate. Approved by the FDA in 2014 for marketing and clinical use in the treatment of acute bacterial skin and skin structure infections. Tedizolid phosphate is a prodrug which can be rapidly converted into biologically active tedizolid by phosphatase in vivo, thereby inhibiting protein synthesis. The action mechanism of the antibiotic is different from other antibiotics, and the antibiotic does not have cross drug resistance with other antibiotics. The traditional Chinese medicine composition is mainly used for treating acute bacterial skin and skin structure infection caused by gram-positive bacteria such as staphylococcus aureus (including methicillin-resistant strains and methicillin-sensitive strains) and various streptococcus and enterococcus faecalis. The chemical structural formula of tedizolid phosphate is shown as follows:
in the process route for synthesizing the tedizolid phosphate bulk drug, a compound 2- (2-methyl-2H-tetrazole-5-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine is an important intermediate, and the chemical structure of the compound is as follows:
in the process of synthesizing the 2- (2-methyl-2H-tetrazole-5-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine intermediate, impurities can be generated, and can participate in the subsequent reaction of the process for synthesizing the tedizolid phosphate raw material medicine to generate more unknown impurities, and can also exist in the tedizolid phosphate raw material medicine independently, so that the product quality is seriously influenced. However, the prior art does not have a public report of the impurity, and also does not have a reference substance of the impurity, so that the content of the impurity cannot be accurately controlled in a process route for synthesizing the tedizolid phosphate bulk drug, and potential safety hazards are brought to the production of the tedizolid phosphate.
The existence of impurities in the raw material medicines can cause the increase of adverse reactions of the preparation and even serious consequences to patients, so that the international and domestic pharmacopoeias stipulate strict limits on the content of the impurities in the raw material medicines. In order to better control the product quality of the tedizolid phosphate bulk drug, it is necessary to prepare the impurity reference substance so as to control the limit of the tedizolid phosphate bulk drug and related important intermediates.
Disclosure of Invention
The invention aims to provide a tedizolid phosphate impurity and a preparation method and application thereof.
The invention provides a tedizolid phosphate impurity, which has a structural formula shown as a formula I:
the invention also provides a preparation method of the tedizolid phosphate impurity, which comprises the following steps:
step 1:
dissolving the compound 1, ammonium chloride and sodium azide in an organic solvent, and reacting to obtain a mixture of a compound 2 and a compound 3;
step 2:
adding dimethylformamide and alkali into the mixture of the compound 2 and the compound 3 obtained in the step 1, vacuumizing, adding an organic solvent and a methylating agent, and reacting to obtain an impurity mixture of a compound 4 and tedizolid phosphate;
and step 3: dissolving the mixture of the compound 4 and the tedizolid phosphate impurities in an organic solvent, adding column chromatography silica gel, and separating by using a preparative liquid chromatography to obtain the tedizolid phosphate impurities.
Further, in the step 1, the reaction is to dissolve the compound 1, ammonium chloride and sodium azide in an organic solvent for a first reaction, and then add the ammonium chloride and the sodium azide for a second reaction;
preferably, the first and second electrodes are formed of a metal,
in step 1, in the first reaction, the molar ratio of compound 1, ammonium chloride and sodium azide is 1: (1-2): (0.8 to 1.5); in the second reaction, the molar ratio of the compound 1, the ammonium chloride added for the second time and the sodium azide is 1: (0.15-0.45): (0.1 to 0.3); the mass-volume ratio of the compound 1 to the organic solvent is 1 g: (8-15) mL;
more preferably, in the step 1, in the first reaction, the molar ratio of the compound 1, the ammonium chloride and the sodium azide is 1 (1.5-1.6) to (0.98-1.15); in the second reaction, the molar ratio of the compound 1, the ammonium chloride added for the second time and the sodium azide is 1: (0.28-0.3): (0.223-0.236); the mass-volume ratio of the compound 1 to the organic solvent is 1 g: (10-12.5) mL;
further preferably, in step 1, in the first reaction, the molar ratio of compound 1, ammonium chloride and sodium azide is 1: 1.5: 1.1; in the second reaction, the molar ratio of the compound 1, the ammonium chloride added for the second time and the sodium azide is 1: 0.3: 0.2; the mass-volume ratio of the compound 1 to the organic solvent is 1 g: 10 mL;
it is still further preferred that the first and second substrates are,
in the step 1, the organic solvent is dimethylformamide;
and/or in the step 1, in the first reaction, the reaction temperature is 70-100 ℃, and the reaction time is 2-6 hours;
and/or in the step 1, in the second reaction, the reaction temperature is 90-120 ℃, and the reaction time is 1-3 hours;
it is still further preferred that the first and second substrates are,
in the step 1, in the first reaction, the reaction temperature is 80-90 ℃, and the reaction time is 3-4 hours;
and/or in the step 1, during the secondary reaction, the reaction temperature is 100-110 ℃, and the reaction time is 2-2.5 hours.
Further, the air conditioner is provided with a fan,
in the step 2, the mass ratio of the mixture of the compound 2 and the compound 3 to the alkali and the methylating agent is 1: (0.25-0.75): (1-2); the mass-to-volume ratio of the mixture of the compound 2 and the compound 3 to the dimethylformamide and the organic solvent is 1 g: (3-6) mL: (4-8) mL;
and/or in the step 3, the mass volume ratio of the impurity mixture of the compound 4 and the tedizolid phosphate to the organic solvent is 1 g: (6-15) mL; the mass ratio of the compound 4 to the tedizolid phosphate impurity mixture to the silica gel is 1: (1-10);
preferably, the first and second electrodes are formed of a metal,
in the step 2, the mass ratio of the mixture of the compound 2 and the compound 3 to the alkali and the methylating agent is 1: (0.5-0.52): (1.4-1.52); the mass-to-volume ratio of the mixture of the compound 2 and the compound 3 to the dimethylformamide and the organic solvent is 1 g: (4-5) mL: (5-6) mL;
and/or in the step 3, the mass volume ratio of the impurity mixture of the compound 4 and the tedizolid phosphate to the organic solvent is 1 g: (10-12) mL; the mass ratio of the compound 4 to the tedizolid phosphate impurity mixture to the silica gel is 1: 3;
more preferably still, the first and second liquid crystal compositions are,
in the step 2, the mass ratio of the mixture of the compound 2 and the compound 3 to the alkali and the methylating agent is 1: 0.5: 1.5; the mass-to-volume ratio of the mixture of the compound 2 and the compound 3 to the dimethylformamide and the organic solvent is 1 g: 4.5 mL: 5.5 mL;
and/or in the step 3, the mass volume ratio of the impurity mixture of the compound 4 and the tedizolid phosphate to the organic solvent is 1 g: 10 mL; the mass ratio of the compound 4 to the tedizolid phosphate impurity mixture to the silica gel is 1: 3.
further, the air conditioner is provided with a fan,
in the step 1, nitrogen is added for protection during the reaction;
and/or in the step 2, stirring and vacuumizing for 3-6 hours at the vacuumizing temperature of 30-50 ℃;
and/or, in the step 2, the alkali is sodium hydroxide;
and/or, in the step 2, the organic solvent is tetrahydrofuran;
and/or, in the step 2, the methylating agent is methyl iodide;
and/or in the step 2, the reaction temperature is 30-60 ℃, and the reaction time is 1-3 hours;
and/or, in the step 2, purifying after the reaction, wherein the purifying steps are as follows: after the reaction is finished, adding pure water for quenching, then adding dichloromethane for extraction, concentrating an organic phase, dissolving a concentrate in hydrochloric acid, adding dichloromethane for separating liquid, adding sodium hydroxide into a water phase until the pH value is more than 14, precipitating a solid, and filtering to obtain the compound;
and/or, in the step 3, the organic solvent is dichloromethane;
preferably, the first and second electrodes are formed of a metal,
and/or in the step 2, stirring and vacuumizing for 3-6 hours at the temperature of 35-40 ℃;
and/or in the step 2, the reaction temperature is 40-50 ℃, and the reaction time is 2-2.5 hours.
Further, the conditions for separation using preparative liquid chromatography are as follows:
separation parameters:
leaching procedure:
further, during the separation by using a preparative liquid chromatography, when an impurity 2- (2-methyl-tetrazole) -5-azido pyridine peak appears in the leacheate, the leacheate is collected until the impurity 2- (2-methyl-tetrazole) -5-azido pyridine peak does not appear in the leacheate, the collected leacheate is uniformly mixed and concentrated to be dry, and the compound is obtained.
The invention also provides application of the tedizolid phosphate impurity shown in the formula I as a reference substance in detecting the content of the impurity shown in the formula I in the tedizolid phosphate;
the invention also provides a method for detecting impurities in tedizolid phosphate, wherein the hydrolyzed impurities are the impurities shown in the formula I, and the detection method is high performance liquid chromatography detection and comprises the following specific steps:
(1) preparing a test solution, and dissolving tedizolid phosphate to be tested to obtain the test solution;
(2) preparing a reference substance solution, and dissolving an impurity reference substance shown in formula I to obtain the impurity reference substance;
(3) respectively sucking the test solution and the reference solution, injecting the solutions into a high performance liquid chromatograph for detection, wherein the chromatographic conditions are as follows:
octadecylsilane chemically bonded silica is used as a filler for the chromatographic column;
the mobile phase consists of a phase A and a phase B, wherein the phase A is sodium dihydrogen phosphate aqueous solution, and the phase B is acetonitrile;
preferably, the first and second electrodes are formed of a metal,
in the step (1), the concentration of the tedizolid phosphate to be detected in the test solution is 0.25-5 g/mL;
and/or in the step (1), the reagent for dissolving the tedizolid phosphate to be detected is a mixed solution of sodium dihydrogen phosphate aqueous solution and acetonitrile in equal volume;
and/or in the step (2), the concentration of the impurity reference substance shown in the formula I in the reference substance solution is 0.5-5 g/mL;
and/or in the step (2), the reagent for dissolving the impurity reference substance is a mixed solution of sodium dihydrogen phosphate aqueous solution and acetonitrile in equal volume;
and/or in the step (3), when the high performance liquid chromatograph is used for detection, the detection wavelength is 280-300 nm; and/or the flow rate is 0.8-2 ml/min; and/or the column temperature is 30-40 ℃; and/or the sample injection amount is 10-30 mul;
more preferably, the concentration of the sodium dihydrogen phosphate aqueous solution is 0.05-0.15 mol/L.
Further, when the high performance liquid chromatograph detects, the mobile phase elution procedure is a gradient elution procedure, and the gradient elution procedure is as follows:
| time (min) | Mobile phase B (%) | Mobile phase A (%) |
| 0.0 | 10 | 90 |
| 10 | 20 | 80 |
| 30 | 30 | 70 |
| 40 | 50 | 50 |
| 41 | 40 | 60 |
| 50 | 15 | 85 |
。
Compared with the prior art, the 2- (2-methyl-tetrazole) -5-azidopyridine and the preparation method thereof have the following advantages:
(1) the invention discovers 2- (2-methyl-tetrazole) -5-azidopyridine which is an impurity of a tedizolid phosphate bulk drug for the first time and discloses a synthesis and separation method thereof for the first time;
(2) the synthesis steps are two steps, the process is simple and stable, and the repeatability is good;
(3) the purity of the synthesis and separation method of the impurity 2- (2-methyl-tetrazole) -5-azidopyridine is higher than 96 percent, and the method meets the quality requirements of impurity reference substances related to national pharmacopoeia and Chinese pharmacopoeia;
(4) the qualified impurity reference substance of the 2- (2-methyl-tetrazole) -5-azidopyridine prepared by the invention can be applied to the quality control of the tedizolid phosphate API, the bulk drugs and the preparation, and can also provide a reliable monitoring means for the process research and promote the process optimization and determination process.
In conclusion, the invention provides a tedizolid phosphate impurity 2- (2-methyl-tetrazole) -5-azidopyridine and a preparation method thereof, wherein the impurity is an impurity generated in the process of synthesizing a 2- (2-methyl-2H-tetrazole-5-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine intermediate, and the impurity can participate in the subsequent reaction of the synthesis process of the tedizolid phosphate bulk drug to generate more unknown impurities, can also exist in the tedizolid phosphate bulk drug independently and seriously affect the product quality. The invention synthesizes and separates the impurities, has the purity higher than 96 percent and meets the quality requirements of impurity reference substances related to national pharmacopoeia and Chinese pharmacopoeia. Meanwhile, the invention provides a method for detecting 2- (2-methyl-tetrazole) -5-azido pyridine serving as an impurity in tedizolid phosphate. The preparation method is simple and stable in preparation process and good in repeatability, can be used for preparing the impurity 2- (2-methyl-tetrazole) -5-azidopyridine reference substance, can be applied to quality control of tedizolid phosphate API, raw material medicines and preparations, can also provide a reliable monitoring means for the process research, promotes the process optimization and determination process, and has a good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is an HPLC chromatogram of 2- (2-methyl-tetrazole) -5-azidopyridine obtained in example 1.
FIG. 2 is an HPLC chromatogram for measuring the impurity content of 2- (2-methyl-tetrazole) -5-azidopyridine in a tedizolid phosphate raw material sample.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products. Part of raw materials and equipment sources are as follows:
(1) raw materials
5-bromo-2-cyanopyridine: manufactured by Beijing Vida chemical Co.
Column chromatography silica gel: xian lan and Xiao scientific and technological New materials, Inc.
Tedizolid phosphate control: lot 2018A06, supplied by Nanxi Red pharmaceuticals, Inc., Yibin.
Tedizolid phosphate starting material samples: batch No. 20190506, available from Nanxi Red pharmaceuticals Ltd, Yibin.
(2) Instrumentation and equipment
High performance liquid chromatograph: shimadzu LC-20 AT;
preparing liquid chromatography: bordetella Technologies, model CHEETAH-MP 20.
Example 1 preparation method of tedizolid phosphate impurity 2- (2-methyl-tetrazole) -5-azidopyridine
(1) Synthesis of 2-tetrazole-5-azido pyridine
The reaction formula is as follows:
500ml of Dimethylformamide (DMF) are added to the reaction flask, the nitrogen is evacuated (nitrogen blanket) and the stirring is switched on. 47.5g (0.26mole) of 5-bromo-2-cyanopyridine, 21g (0.39mole) of ammonium chloride and 19g (0.29mole) of sodium azide are added, the temperature is slowly raised to 80-90 ℃ for reaction for 3 hours, and 4.2g (0.078mole) of ammonium chloride and 3.8g (0.058mole) of sodium azide are added for reaction for 2 hours at 100-110 ℃. Cooling to room temperature, and filtering to obtain 65.6g of a mixture of 2-tetrazole-5-bromopyridine/2-tetrazole-5-azidopyridine for later use.
(2) Synthesis of 2- (2-methyl-tetrazole) -5-azido pyridine
The reaction formula is as follows:
adding 65.6g of 2-tetrazole-5-bromopyridine/2-tetrazole-5-azidopyridine mixture into a reaction bottle, adding 300ml of dimethylformamide and 33g of sodium hydroxide, stirring at 40 ℃, vacuumizing for 3 hours, wherein the system becomes white and turbid, and the next operation can be carried out when the pH is tested to be less than 13 and no large ammonia odor exists.
Adding 360ml of tetrahydrofuran, dropwise adding 100g (0.7mole) of methyl iodide, keeping the temperature of 40-50 ℃ for reacting for 2 hours after dropwise adding, dissolving the system clearly, adding 800ml of pure water to quench the reaction, then extracting with 400ml of dichloromethane, separating out an organic phase, concentrating to be dry, dissolving the concentrate in 400ml of 6N hydrochloric acid, adding 200ml of dichloromethane for liquid separation, adding sodium hydroxide into a water phase until the pH value is higher than 14, separating out a solid, and filtering to obtain 23g of a crude 2- (2-methyl-tetrazole) -5-azidopyridine/2- (2-methyl-tetrazole) -5-bromopyridine mixture.
(3) Separation method of 2- (2-methyl-tetrazole) -5-azido pyridine
5g of the crude mixture of 2- (2-methyl-tetrazole) -5-azidopyridine and 2- (2-methyl-tetrazole) -5-bromopyridine obtained in the step (2) is dissolved in 50ml of dichloromethane, 15g of a sample is obtained by column chromatography silica gel dry method, and the crude product is separated and prepared by a preparation chromatograph of Bordetella Agela Technologies (model number CHEETAH-MP 2).
Agela Technologies (model CHEETAH-MP2) parameter settings:
separation parameters:
leaching procedure:
| B％ | start of | End up | Duration of time |
| Equivalence ratio | 8.0 | 8.0 | 10.0 |
| 1 | 8.0 | 47.5 | 56.4 |
| 2 | 47.5 | 50.0 | 3.7 |
| 3 | 50.0 | 100.0 | 9.9 |
Collecting after separation of the prepared liquid phase chromatography, displaying that the chromatographic peak height of the impurity 2- (2-methyl-tetrazole) -5-azido pyridine appears from a No. 38 test tube, until the chromatographic peak height of the impurity 2- (2-methyl-tetrazole) -5-azido pyridine appears in a No. 81 test tube, collecting No. 38-80 test tube components containing the impurity 2- (2-methyl-tetrazole) -5-azido pyridine, uniformly mixing, concentrating to be dry, obtaining 760mg of 2- (2-methyl-tetrazole) -5-azido pyridine, and determining the purity, wherein the purity is 96.3%, and the purity meets the requirements of national formulary and Chinese formulary on impurity quality standards. The structural formula of the 2- (2-methyl-tetrazole) -5-azido pyridine is as follows:
the product 2- (2-methyl-tetrazole) -5-azidopyridine obtained in the example is carried out1HNMR mapping, analysis was as follows:
1H NMR(400MHz,CDCl3)：8.48(d,J＝2.4Hz,1H),8.23(d,J＝8.5Hz,1H),7.51(dd,J＝8.5,2.5Hz,1H),4.44(s,3H)。
the product 2- (2-methyl-tetrazole) -5-azidopyridine obtained in the example was subjected to MS spectrum analysis as follows:
MS(ES):m/z＝203[M+H]+,175[M-N2+H]+。
FIG. 1 shows the HPLC purity map of the product 2- (2-methyl-tetrazole) -5-azidopyridine obtained in example 1, with a purity of 96.3%.
Example 2 preparation method of tedizolid phosphate impurity 2- (2-methyl-tetrazole) -5-azidopyridine
(1) Synthesis of 2-tetrazole-5-azido pyridine
The reaction formula is as follows:
1000ml of Dimethylformamide (DMF) are added to the reaction flask, the nitrogen is evacuated (nitrogen blanket) and the stirring is switched on. Adding 80g of 5-bromo-2-cyanopyridine, 38g of ammonium chloride and 28g of sodium azide, slowly heating to 85-90 ℃ for reaction for 4 hours, and supplementing 6.7g of ammonium chloride and 6.8g of sodium azide for reaction for 2.5 hours at 100-110 ℃. And cooling to room temperature, and filtering to obtain a mixture of 112g of 2-tetrazole-5-bromopyridine/2-tetrazole-5-azidopyridine for later use.
(2) Synthesis of 2- (2-methyl-tetrazole) -5-azido pyridine
The reaction formula is as follows:
adding 100g of 2-tetrazole-5-bromopyridine/2-tetrazole-5-azidopyridine mixture into a reaction bottle, adding 500ml of dimethylformamide and 52g of sodium hydroxide, stirring at 40 ℃, vacuumizing for 3 hours, wherein the system becomes white and turbid, and the next operation can be carried out when the pH is tested to be less than 13 and no large ammonia odor exists.
Adding 600ml of tetrahydrofuran, dropwise adding 140g of methyl iodide, keeping the temperature of 40-45 ℃ for reaction for 2.5 hours after dropwise adding, dissolving the system clearly, adding 1000ml of pure water to quench the reaction, then extracting with 500ml of dichloromethane, separating out an organic phase, concentrating to be dry, dissolving the concentrate in 500ml of 6N hydrochloric acid, adding 250ml of dichloromethane for liquid separation, adding sodium hydroxide into a water phase until the pH value is more than 14, separating out a solid, and filtering to obtain 36g of a crude mixture of 2- (2-methyl-tetrazole) -5-azidopyridine/2- (2-methyl-tetrazole) -5-bromopyridine.
(3) Separation method of 2- (2-methyl-tetrazole) -5-azido pyridine
5g of the crude mixture of 2- (2-methyl-tetrazole) -5-azidopyridine and 2- (2-methyl-tetrazole) -5-bromopyridine obtained in the step (2) is dissolved in 60ml of dichloromethane, 15g of the sample is taken by column chromatography silica gel dry method, and the product is separated and prepared by a preparation chromatograph of Bonaejel Agela Technologies (model number CHEETAH-MP 2). The separation parameters and washing procedure were the same as in example 1.
The test tube number of the collected effective components is the same as that of the test tube number of the example 1, the test tube number is concentrated to be dry, 772mg of 2- (2-methyl-tetrazole) -5-azido pyridine is obtained, the purity is measured to be 96.5 percent, and the test tube number accords with the requirements of national pharmacopoeia and Chinese pharmacopoeia on impurity quality standards.
Example 3 quality control of Tedizolid phosphate starting Material was studied using 2- (2-methyl-tetrazol) -5-azidopyridine as a control
(1) Preparing a diluent: 0.05mol/L sodium dihydrogen phosphate water solution is used as a mobile phase A, and acetonitrile is used as a mobile phase B. Mixing A and B with the same volume, and shaking up to obtain the diluent.
(2) 12.5mg of tedizolid phosphate reference substance (batch number 2018A 06), 25mg of 2- (2-methyl-tetrazole) -5-azido pyridine reference substance prepared in example 1 are precisely weighed, placed in a 50ml measuring flask, added with 10 drops of saturated sodium bicarbonate and 1ml of dimethyl sulfoxide for dissolution, diluted by diluent until scales are evenly shaken to obtain a system solution.
(3) 12.5mg of tedizolid phosphate raw material medicine sample (batch number 20190506) is precisely weighed and placed in a 50ml measuring flask, 10 drops of saturated sodium bicarbonate are added for dissolution, and then diluted by diluent until scales are evenly shaken to be used as a test solution.
(4) Chromatographic conditions
Octadecylsilane chemically bonded silica is used as a filler, 0.05mol/L sodium dihydrogen phosphate aqueous solution is used as a mobile phase A, and acetonitrile is used as a mobile phase B. The flow rate was 0.8ml/min, the column temperature was 30 ℃, the detection wavelength was 300nm, and the dilution A: B (50:50) v/v. The distribution of the gradient elution is as follows:
| time (min) | Mobile phase B (%) | Mobile phase A (%) |
| 0.0 | 10 | 90 |
| 10 | 20 | 80 |
| 30 | 30 | 70 |
| 40 | 50 | 50 |
| 41 | 40 | 60 |
| 50 | 15 | 85 |
(5) Measurement of
The measurement is carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition of the general rules 0512 in four parts). Precisely measuring the diluent, the system solution and the sample solution, respectively 10 μ l, injecting into a liquid chromatograph, recording chromatogram (see figure 2), wherein if the sample solution chromatogram has an impurity peak of 2- (2-methyl-tetrazole) -5-azido pyridine, the blank solvent peak is deducted according to area normalization.
(6) Measurement results
According to the calculation of an area normalization method, the content of 2- (2-methyl-tetrazole) -5-azidopyridine impurities in the tedizolid phosphate raw material sample is 0.012%.
The content of the impurity 2- (2-methyl-tetrazole) -5-azidopyridine is less than 0.1 percent, and the impurity meets the quality requirements of United states pharmacopoeia, European Union pharmacopoeia, British pharmacopoeia and 2015 edition of Chinese pharmacopoeia.
In conclusion, the invention provides a tedizolid phosphate impurity 2- (2-methyl-tetrazole) -5-azidopyridine and a preparation method thereof, wherein the impurity is an impurity generated in the process of synthesizing a 2- (2-methyl-2H-tetrazole-5-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine intermediate, and the impurity can participate in the subsequent reaction of the synthesis process of the tedizolid phosphate bulk drug to generate more unknown impurities, can also exist in the tedizolid phosphate bulk drug independently and seriously affect the product quality. The invention synthesizes and separates the impurities, has the purity higher than 96 percent and meets the quality requirements of impurity reference substances related to national pharmacopoeia and Chinese pharmacopoeia. Meanwhile, the invention provides a method for detecting 2- (2-methyl-tetrazole) -5-azido pyridine serving as an impurity in tedizolid phosphate. The preparation method is simple and stable in preparation process and good in repeatability, can be used for preparing the impurity 2- (2-methyl-tetrazole) -5-azidopyridine reference substance, can be applied to quality control of tedizolid phosphate API, raw material medicines and preparations, can also provide a reliable monitoring means for the process research, promotes the process optimization and determination process, and has a good application prospect.
Claims (10)
1. An impurity of tedizolid phosphate, characterized in that: the structural formula of the impurity is shown as formula I:
2. a method for preparing tedizolid phosphate impurity according to claim 1, characterized in that: the preparation method comprises the following steps:
step 1:
dissolving the compound 1, ammonium chloride and sodium azide in an organic solvent, and reacting to obtain a mixture of a compound 2 and a compound 3;
step 2:
adding dimethylformamide and alkali into the mixture of the compound 2 and the compound 3 obtained in the step 1, vacuumizing, adding an organic solvent and a methylating agent, and reacting to obtain an impurity mixture of a compound 4 and tedizolid phosphate;
and step 3: dissolving the mixture of the compound 4 and the tedizolid phosphate impurities in an organic solvent, adding column chromatography silica gel, and separating by using a preparative liquid chromatography to obtain the tedizolid phosphate impurities.
3. The method of claim 2, wherein: in the step 1, dissolving a compound 1, ammonium chloride and sodium azide in an organic solvent to carry out a first reaction, and then adding the ammonium chloride and the sodium azide to carry out a second reaction;
preferably, the first and second electrodes are formed of a metal,
in step 1, in the first reaction, the molar ratio of compound 1, ammonium chloride and sodium azide is 1: (1-2): (0.8 to 1.5); in the second reaction, the molar ratio of the compound 1, the ammonium chloride added for the second time and the sodium azide is 1: (0.15-0.45): (0.1 to 0.3); the mass-volume ratio of the compound 1 to the organic solvent is 1 g: (8-15) mL;
more preferably, in the step 1, in the first reaction, the molar ratio of the compound 1, the ammonium chloride and the sodium azide is 1 (1.5-1.6) to (0.98-1.15); in the second reaction, the molar ratio of the compound 1, the ammonium chloride added for the second time and the sodium azide is 1: (0.28-0.3): (0.223-0.236); the mass-volume ratio of the compound 1 to the organic solvent is 1 g: (10-12.5) mL;
further preferably, in step 1, in the first reaction, the molar ratio of compound 1, ammonium chloride and sodium azide is 1: 1.5: 1.1; in the second reaction, the molar ratio of the compound 1, the ammonium chloride added for the second time and the sodium azide is 1: 0.3: 0.2; the mass-volume ratio of the compound 1 to the organic solvent is 1 g: 10 mL;
it is still further preferred that the first and second substrates are,
in the step 1, the organic solvent is dimethylformamide;
and/or in the step 1, in the first reaction, the reaction temperature is 70-100 ℃, and the reaction time is 2-6 hours;
and/or in the step 1, in the second reaction, the reaction temperature is 90-120 ℃, and the reaction time is 1-3 hours;
it is still further preferred that the first and second substrates are,
in the step 1, in the first reaction, the reaction temperature is 80-90 ℃, and the reaction time is 3-4 hours;
and/or in the step 1, during the secondary reaction, the reaction temperature is 100-110 ℃, and the reaction time is 2-2.5 hours.
4. The method of claim 2, wherein:
in the step 2, the mass ratio of the mixture of the compound 2 and the compound 3 to the alkali and the methylating agent is 1: (0.25-0.75): (1-2); the mass-to-volume ratio of the mixture of the compound 2 and the compound 3 to the dimethylformamide and the organic solvent is 1 g: (3-6) mL: (4-8) mL;
and/or in the step 3, the mass volume ratio of the impurity mixture of the compound 4 and the tedizolid phosphate to the organic solvent is 1 g: (6-15) mL; the mass ratio of the compound 4 to the tedizolid phosphate impurity mixture to the silica gel is 1: (1-10);
preferably, the first and second electrodes are formed of a metal,
in the step 2, the mass ratio of the mixture of the compound 2 and the compound 3 to the alkali and the methylating agent is 1: (0.5-0.52): (1.4-1.52); the mass-to-volume ratio of the mixture of the compound 2 and the compound 3 to the dimethylformamide and the organic solvent is 1 g: (4-5) mL: (5-6) mL;
and/or in the step 3, the mass volume ratio of the impurity mixture of the compound 4 and the tedizolid phosphate to the organic solvent is 1 g: (10-12) mL; the mass ratio of the compound 4 to the tedizolid phosphate impurity mixture to the silica gel is 1: 3;
more preferably still, the first and second liquid crystal compositions are,
in the step 2, the mass ratio of the mixture of the compound 2 and the compound 3 to the alkali and the methylating agent is 1: 0.5: 1.5; the mass-to-volume ratio of the mixture of the compound 2 and the compound 3 to the dimethylformamide and the organic solvent is 1 g: 4.5 mL: 5.5 mL;
and/or in the step 3, the mass volume ratio of the impurity mixture of the compound 4 and the tedizolid phosphate to the organic solvent is 1 g: 10 mL; the mass ratio of the compound 4 to the tedizolid phosphate impurity mixture to the silica gel is 1: 3.
5. the method of claim 2, wherein:
in the step 1, nitrogen is added for protection during the reaction;
and/or in the step 2, stirring and vacuumizing for 3-6 hours at the vacuumizing temperature of 30-50 ℃;
and/or, in the step 2, the alkali is sodium hydroxide;
and/or, in the step 2, the organic solvent is tetrahydrofuran;
and/or, in the step 2, the methylating agent is methyl iodide;
and/or in the step 2, the reaction temperature is 30-60 ℃, and the reaction time is 1-3 hours;
and/or, in the step 2, purifying after the reaction, wherein the purifying steps are as follows: after the reaction is finished, adding pure water for quenching, then adding dichloromethane for extraction, concentrating an organic phase, dissolving a concentrate in hydrochloric acid, adding dichloromethane for separating liquid, adding sodium hydroxide into a water phase until the pH value is more than 14, precipitating a solid, and filtering to obtain the compound;
and/or, in the step 3, the organic solvent is dichloromethane;
preferably, the first and second electrodes are formed of a metal,
and/or in the step 2, stirring and vacuumizing for 3-6 hours at the temperature of 35-40 ℃;
and/or in the step 2, the reaction temperature is 40-50 ℃, and the reaction time is 2-2.5 hours.
6. The production method according to any one of claims 2 to 5, characterized in that: the conditions for separation using preparative liquid chromatography were as follows:
separation parameters:
leaching procedure:
7. the production method according to any one of claims 2 to 5, characterized in that: when the preparation liquid chromatography is used for separation, the collection is started when the impurity 2- (2-methyl-tetrazole) -5-azido pyridine peak appears in the leacheate, the collected leacheate is uniformly mixed until the impurity 2- (2-methyl-tetrazole) -5-azido pyridine peak does not appear in the leacheate, and the concentration is carried out till the impurities are dry, so that the preparation liquid is obtained.
8. The use of the tedizolid phosphate impurity shown in the formula I as a reference substance in detecting the content of the impurity shown in the formula I in the tedizolid phosphate;
9. a method for detecting impurities in tedizolid phosphate is characterized by comprising the following steps: the hydrolysis impurities are impurities shown in a formula I, and the detection method is high performance liquid chromatography detection and comprises the following specific steps:
(1) preparing a test solution, and dissolving tedizolid phosphate to be tested to obtain the test solution;
(2) preparing a reference substance solution, and dissolving an impurity reference substance shown in formula I to obtain the impurity reference substance;
(3) respectively sucking the test solution and the reference solution, injecting the solutions into a high performance liquid chromatograph for detection, wherein the chromatographic conditions are as follows:
octadecylsilane chemically bonded silica is used as a filler for the chromatographic column;
the mobile phase consists of a phase A and a phase B, wherein the phase A is sodium dihydrogen phosphate aqueous solution, and the phase B is acetonitrile;
preferably, the first and second electrodes are formed of a metal,
in the step (1), the concentration of the tedizolid phosphate to be detected in the test solution is 0.25-5 g/mL;
and/or in the step (1), the reagent for dissolving the tedizolid phosphate to be detected is a mixed solution of sodium dihydrogen phosphate aqueous solution and acetonitrile in equal volume;
and/or in the step (2), the concentration of the impurity reference substance shown in the formula I in the reference substance solution is 0.5-5 g/mL;
and/or in the step (2), the reagent for dissolving the impurity reference substance is a mixed solution of sodium dihydrogen phosphate aqueous solution and acetonitrile in equal volume;
and/or in the step (3), when the high performance liquid chromatograph is used for detection, the detection wavelength is 280-300 nm; and/or the flow rate is 0.8-2 ml/min; and/or the column temperature is 30-40 ℃; and/or the sample injection amount is 10-30 mul;
more preferably, the concentration of the sodium dihydrogen phosphate aqueous solution is 0.05-0.15 mol/L.
10. The detection method according to claim 9, characterized in that: when the high performance liquid chromatograph is used for detection, the mobile phase elution procedure is a gradient elution procedure which is as follows:
。
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| CN114716391A (en) * | 2022-04-24 | 2022-07-08 | 杭州仟源保灵药业有限公司 | Methazolamide impurity and preparation method and application thereof |
| CN115792047A (en) * | 2023-02-10 | 2023-03-14 | 四川美域高生物医药科技有限公司 | Method for detecting tedizolid phosphate intermediate related substances |
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| CN106565680A (en) * | 2016-10-31 | 2017-04-19 | 瑞阳制药有限公司 | Tedizolid impurity and preparing method thereof |
| CN107121503A (en) * | 2017-03-14 | 2017-09-01 | 南京优科制药有限公司 | A kind of Tedizolid Phosphate and its analysis method about material |
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| WO2016009401A2 (en) * | 2014-07-18 | 2016-01-21 | Dr. Reddy's Laboratories Limited | Preparation of tedizolid phosphate |
| CN106565680A (en) * | 2016-10-31 | 2017-04-19 | 瑞阳制药有限公司 | Tedizolid impurity and preparing method thereof |
| CN107121503A (en) * | 2017-03-14 | 2017-09-01 | 南京优科制药有限公司 | A kind of Tedizolid Phosphate and its analysis method about material |
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| CN114716391A (en) * | 2022-04-24 | 2022-07-08 | 杭州仟源保灵药业有限公司 | Methazolamide impurity and preparation method and application thereof |
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