CN105837634B - Tedizolid phosphate crystal and preparation method thereof - Google Patents
Tedizolid phosphate crystal and preparation method thereof Download PDFInfo
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- CN105837634B CN105837634B CN201610051458.9A CN201610051458A CN105837634B CN 105837634 B CN105837634 B CN 105837634B CN 201610051458 A CN201610051458 A CN 201610051458A CN 105837634 B CN105837634 B CN 105837634B
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- 239000013078 crystal Substances 0.000 title claims abstract description 124
- 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 102
- 229960003947 tedizolid phosphate Drugs 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 34
- 238000012360 testing method Methods 0.000 claims abstract description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 48
- 239000003960 organic solvent Substances 0.000 claims description 29
- 239000011259 mixed solution Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 26
- 238000001816 cooling Methods 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 230000001502 supplementing effect Effects 0.000 claims description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000012296 anti-solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000005286 illumination Methods 0.000 abstract description 10
- 238000002474 experimental method Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 238000002411 thermogravimetry Methods 0.000 description 15
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004455 differential thermal analysis Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000013094 purity test Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- -1 (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one dihydrogen phosphate ester Chemical class 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 229910000838 Al alloy Inorganic materials 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a tedizolid phosphate crystal and a preparation method thereof, the crystal has main characteristic peaks at diffraction angles 2 theta of 11.9 degrees, 13.8 degrees, 14.8 degrees, 15.4 degrees, 15.6 degrees, 16.3 degrees, 17.1 degrees, 20.7 degrees, 20.9 degrees, 22.0 degrees, 23.8 degrees, 24.5 degrees and 27.5 degrees under X-ray powder diffraction, and the test error is +/-0.2 degrees; the main characteristic peak is a peak with the relative intensity of more than or equal to 20 percent. Experiments prove that: the tedizolid phosphate crystal provided by the invention has high stability under high humidity, heat and illumination, has remarkably improved solubility in water, is very suitable for application and production of pharmaceutical preparations, and has obvious industrial application value.
Description
Technical Field
The invention relates to a tedizolid phosphate crystal and a preparation method thereof, belonging to the technical field of pharmaceutical chemistry.
Background
Tedizolid Phosphate (Tedizolid Phosphate) is a second generation oxazolidinone antibiotic and has been approved by the FDA in the market in 2014 on 20/06 months. The chemical name of tedizolid phosphate is as follows: (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one dihydrogen phosphate ester of the formula: c17H16FN6O6P, molecular weight 450.32, CAS number 856867-55-5, its structural formula is:
methods for the preparation of tedizolid phosphate and disodium tedizolid phosphate are disclosed in international patent document WO2005058886a1, but they do not show stable crystallization or purification.
In international patent document WO2010091131a1, a tedizolid phosphate crystal (known in the art as form i) is disclosed, which has X-ray powder diffraction data shown in table 1:
DSC shows that the melting point of the crystal is about 255-258 ℃ (256.9 ℃). Although the experiment shows that the crystal is relatively stable and has no hygroscopicity, the crystal is easy to form particles, so that the filtration treatment is difficult; particularly, the solubility of the crystal in water is only 0.1mg/mL, and the water solubility is too poor to be absorbed by human bodies.
To solve the problem of poor water solubility of tedizolid phosphate, WO2015158202a1 discloses a crystalline tedizolid phosphate (referred to herein as form ii) having X-ray powder diffraction data shown in table 2:
it is disclosed that the crystalline form (form II) has a solubility in water of 168. mu.g/mL, whereas form I has a solubility in water of only 118. mu.g/mL. Although the solubility of the crystal form II in water is improved compared with that of the crystal form I, the improvement is not obvious, and the problems of poor water solubility and unfavorable absorption and utilization by a human body still exist.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a tedizolid phosphate crystal with good solubility, thermal stability, high humidity stability and pressure stability and a preparation method thereof, so as to meet the requirements of subsequent preparation development and large-scale production.
The tedizolid phosphate crystal provided by the invention has main characteristic peaks at diffraction angles 2 theta of 11.9 degrees, 13.8 degrees, 14.8 degrees, 15.4 degrees, 15.6 degrees, 16.3 degrees, 17.1 degrees, 20.7 degrees, 20.9 degrees, 22.0 degrees, 23.8 degrees, 24.5 degrees and 27.5 degrees under X-ray powder diffraction, and the test error is +/-0.2 degrees.
Furthermore, the tedizolid phosphate crystal provided by the invention has characteristic peaks at diffraction angles 2 theta of 10.4, 10.9, 11.9, 13.8, 14.8, 15.4, 15.6, 16.3, 17.1, 17.7, 19.1, 20.0, 20.7, 20.9, 21.3, 22.0, 22.9, 23.8, 24.5, 26.3, 27.5, 28.8 and 33.9 under X-ray powder diffraction, and the test error is +/-0.2 degrees.
Furthermore, the tedizolid phosphate crystal provided by the invention has an X-ray powder diffraction spectrum shown in figure 1, wherein the characteristic peak data is shown in Table 3:
the term "main characteristic peak" as used herein means a peak having a relative intensity of 20% or more.
The term "characteristic peak" as used herein means a peak having a relative intensity of > 5%.
The method for preparing the tedizolid phosphate crystal comprises the following steps:
a) concentrating a mixed solution formed by tedizolid phosphate, an organic solvent and water to 1/3-2/3 (preferably 1/2) of the original volume at 30-50 ℃ (preferably 40-45 ℃); the organic solvent is selected from any one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone, ethyl acetate and thionyl chloride (preferably tetrahydrofuran, N-dimethylformamide or thionyl chloride); the volume ratio of the organic solvent to the water is 100: 1-1: 1 (preferably 60: 1 to 1: 1); the content of tedizolid phosphate in the mixed solution is 0.01-1.0 g/mL;
b) cooling to 0-10 ℃, dropwise adding an anti-solvent into the mixed solution concentrated in the step a) until the mixed solution is turbid, and stirring for 1-3 hours while keeping the temperature; the antisolvent is selected from any one of methyl tert-butyl ether, isopropyl ether, n-hexane, cyclopentane and n-pentane (preferably n-hexane);
c) and (3) filtering, collecting precipitated crystals, and drying at 40-90 ℃ (preferably drying at 50-60 ℃) in vacuum to obtain tedizolid phosphate crystals.
The mixed solution in the step a) can be prepared by directly dissolving tedizolid phosphate raw material in an organic solvent and water according to the volume ratio of 100: 1-1: 1 (preferably 60: 1-1: 1) in a mixed solvent; or dissolving tedizolid phosphate disodium salt in water and the organic solvent according to the volume ratio of 50: 1-1: 1, adding the same organic solvent after acidification until the volume ratio of the organic solvent to water in the system is 100: 1-1: 1 to obtain the compound.
The other method for preparing the tedizolid phosphate crystal comprises the following steps:
A) completely dissolving the tedizolid phosphate raw material in a solvent at 30-100 ℃ (preferably 50-80 ℃); the solvent is an organic solvent or the volume ratio of the organic solvent to water is 100: 1-1: 10 (preferably 10: 1 to 1: 1); the organic solvent is an organic amine solvent or an amide solvent, and includes but is not limited to N, N-dimethylformamide, N-dimethylacetamide and pyridine (preferably N, N-dimethylformamide);
B) naturally cooling the solution obtained in the step A to 40-60 ℃ (preferably to 45-55 ℃), and stirring for 1-3 hours under heat preservation; then naturally cooling to 0-10 ℃ (preferably 1-6 ℃) while stirring;
C) and (3) filtering, collecting precipitated crystals, and drying at 40-90 ℃ (preferably drying at 50-60 ℃) in vacuum to obtain tedizolid phosphate crystals.
The method for preparing the tedizolid phosphate crystal comprises the following steps:
at the temperature of 20-40 ℃, the tedizolid phosphate disodium salt is completely dissolved in an organic solvent and water according to the volume ratio of 100: 1-1: 100 (preferably 1: 5 to 1: 10) in a mixed solvent; the organic solvent is an organic amine solvent or an amide solvent, and includes but is not limited to N, N-dimethylformamide, N-dimethylacetamide and pyridine (preferably N, N-dimethylformamide);
secondly, acidifying the solution obtained in the step one to ensure that the pH of the solution is 0.5-4 (preferably 1.5-2.5);
supplementing the organic solvent which is the same as the organic solvent in the step I, and enabling the volume ratio of the organic solvent to water in the solution system to be 100: 1-1: 100 (preferably 2: 1-4: 1), and then heating to 60-80 ℃ to obtain a clear solution;
fourthly, naturally cooling the solution obtained in the third step to 40-60 ℃ (preferably 45-55 ℃), and stirring for 1-3 hours while keeping the temperature; then naturally cooling to 0-10 ℃ (preferably 1-6 ℃) while stirring;
fifthly, filtering and collecting precipitated crystals, and drying at 40-90 ℃ (preferably drying at 50-60 ℃) in vacuum to obtain the tedizolid phosphate crystal.
The tedizolid phosphate raw material and the tedizolid phosphate disodium salt are in any known forms.
Experiments prove that: the tedizolid phosphate crystal provided by the invention is stable in form, easy to filter and separate, high in purity and stable in quality, has thermal stability, high humidity stability and pressure stability, and has the solubility in water improved from 0.1mg/mL to 0.8mg/mL in the prior art; and the preparation process is simple, easy to operate and scale-up, beneficial to development and scale production of subsequent preparations, and has industrial application value.
Drawings
FIG. 1 is an X-ray powder diffraction (XRD) spectrum of tedizolid phosphate crystal obtained by the invention;
FIG. 2 is a differential thermal analysis (DSC) spectrum of tedizolid phosphate crystal obtained by the invention;
FIG. 3 is a thermogravimetric analysis (TGA) spectrum of tedizolid phosphate crystal obtained by the present invention;
FIG. 4 is an X-ray powder diffraction (XRD) pattern of tedizolid phosphate crystal (referred to as crystal form I in the prior art) prepared in comparative example 1.
FIG. 5 is an X-ray powder diffraction (XRD) spectrum of tedizolid phosphate crystal (referred to as crystal form II in the prior art) prepared in comparative example 2.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to the accompanying drawings and examples.
The tedizolid phosphate raw material and the tedizolid phosphate disodium salt used in the examples are prepared by the methods described in Chinese patent CN102439006A examples 1-9 and patent CN102177156A example 8 respectively.
The X-ray powder diffraction (XRD) spectrum obtained by the invention is 1.5460 angstroms
α of11.54439 angstroms (A)
α of2Intensity ratio α1/α2Measured and analyzed in Dedye-Scherrer INEL CPS-120 equipment with voltage of 0.5, 40kV and current intensity of 30 mA. It will be understood by those skilled in the art that X-ray powder diffraction analysis depends on the measurement conditions used, and that X-ray powder diffraction patterns obtained under different measurement conditions may have certain measurement errors. In particular, in general, the intensity in the X-ray powder diffraction pattern may fluctuate depending on the test conditions. It should be further understood that the relative intensities may also vary from experimental condition to experimental condition, and therefore, the precise numerical value of the intensity should not be considered. Further, for a conventional X-ray powder diffraction pattern, the measurement error of the diffraction angle is typically about 5% or less, and for the above-mentioned diffraction angles, such a degree of measurement error should be considered.
The obtained differential thermal analysis (DSC) spectrogram is obtained by introducing 50mL/min nitrogen flow into a closed container, measuring and analyzing in DSC Q2000 (American TA) equipment at the temperature of 20-450 ℃ and the heating rate of 10 ℃/min.
Thermogravimetric analysis (TGA) spectrogram obtained by the invention is obtained by analyzing on a TA instrument TGA2050, and the calibration standard is nickel and nickel-aluminum alloy; the sample was heated at a rate of 10 deg.C/min under nitrogen to a final temperature of 300 deg.C.
The conditions for HPLC purity test analysis according to the present invention are as follows:
example 1
Dissolving 1.0g of tedizolid phosphate raw material in a mixed solvent formed by 30mL of N, N-dimethylformamide and 0.5mL of water at 60 ℃ to obtain a colorless to light yellow mixed solution;
concentrating the above mixed solution to half of the original volume (about 15mL) at 45 ℃;
slowly cooling to 1 ℃, then slowly adding n-hexane until turbidity appears, and stirring for 2 hours under heat preservation to crystallize;
filtering, collecting precipitated crystals, and vacuum drying at 50 ℃ to obtain 0.9g of tedizolid phosphate crystal with the HPLC purity of 99.90%; DSC showed a melting point of 234 ℃.
FIG. 1 is an XRD spectrum of tedizolid phosphate crystal obtained by the invention, and can be seen from FIG. 1: under X-ray powder diffraction, the crystal has main characteristic peaks at diffraction angles 2 theta of 11.9 degrees, 13.8 degrees, 14.8 degrees, 15.4 degrees, 15.6 degrees, 16.3 degrees, 17.1 degrees, 20.7 degrees, 20.9 degrees, 22.0 degrees, 23.8 degrees, 24.5 degrees and 27.5 degrees; characteristic peaks exist at diffraction angles 2 theta of 10.4, 10.9, 11.9 degrees, 13.8 degrees, 14.8 degrees, 15.4 degrees, 15.6 degrees, 16.3 degrees, 17.1 degrees, 17.7 degrees, 19.1 degrees, 20.0 degrees, 20.7 degrees, 20.9 degrees, 21.3 degrees, 22.0 degrees, 22.9 degrees, 23.8 degrees, 24.5 degrees, 26.3 degrees, 27.5 degrees, 28.8 degrees and 33.9 degrees, and the test error is +/-0.2 degrees; the characteristic peak data therein are specifically shown below:
FIG. 2 is a DSC spectrum of tedizolid phosphate crystal obtained by the invention, and the DSC spectrum can be seen from the chart 2: the crystal disclosed by the invention has a melting endothermic peak at 230-237 ℃ (specifically 235.1 ℃).
FIG. 3 is a TGA spectrum of the tedizolid phosphate crystal obtained by the invention, and the TGA spectrum can be seen from FIG. 3: the crystal is an anhydrous substance.
Example 2
Dissolving 1.0g of tedizolid phosphate raw material in a mixed solvent formed by 50mL of tetrahydrofuran and 50mL of water at 50 ℃ to obtain a light yellow mixed solution;
concentrating the above mixed solution to half of the original volume (about 50mL) at 40 deg.C;
slowly cooling to 10 ℃, then slowly adding n-hexane until turbidity appears, and stirring for 2 hours at the constant temperature to crystallize;
filtering, collecting precipitated crystals, and drying at 50 ℃ in vacuum to obtain 0.89g of tedizolid phosphate crystal with the HPLC purity of 99.7%; DSC showed a melting point of 236 ℃.
The tedizolid phosphate crystal obtained in the embodiment also has the XRD spectrum characteristic shown in figure 1, the DSC spectrum characteristic shown in figure 2 and the TGA spectrum characteristic shown in figure 3.
Example 3
Dissolving 1.0g of tedizolid phosphate raw material in a mixed solvent formed by 10mL of thionyl chloride and 0.2mL of water at 45 ℃ to obtain a light yellow mixed solution;
concentrating the above mixed solution to half of the original volume (about 5mL) at 40 deg.C;
slowly cooling to 5 ℃, then slowly adding n-hexane until turbidity appears, and stirring for 2 hours under heat preservation to crystallize;
filtering, collecting precipitated crystals, and drying at 50 ℃ in vacuum to obtain 0.91g of tedizolid phosphate crystal with the HPLC purity of 99.75%; DSC showed a melting point of 233 ℃.
The tedizolid phosphate crystal obtained in the embodiment also has the XRD spectrum characteristic shown in figure 1, the DSC spectrum characteristic shown in figure 2 and the TGA spectrum characteristic shown in figure 3.
Example 4
Dissolving 1.0g of tedizolid phosphate raw material in a mixed solvent formed by 60mL of N, N-dimethylformamide and 5mL of water at 30 ℃ to obtain a light yellow mixed solution;
concentrating the above mixed solution to half of the original volume (about 32mL) at 45 ℃;
slowly cooling to 1 ℃, then slowly adding n-hexane until turbidity appears, and stirring for 2 hours under heat preservation to crystallize;
filtering, collecting precipitated crystals, and drying at 50 ℃ in vacuum to obtain 0.84g of tedizolid phosphate crystal with the HPLC purity of 99.79%; DSC showed a melting point of 234 ℃.
The tedizolid phosphate crystal obtained in the embodiment also has the XRD spectrum characteristic shown in figure 1, the DSC spectrum characteristic shown in figure 2 and the TGA spectrum characteristic shown in figure 3.
Example 5
Firstly, dissolving 1g of tedizolid phosphate disodium salt in a mixed solvent formed by 10mL of water and 4mL of N, N-dimethylformamide at room temperature, acidifying (adding hydrochloric acid to adjust the pH value of the solution to be 2.5), supplementing 15mL of N, N-dimethylformamide, and heating to 80 ℃ to obtain a colorless-light yellow mixed solution;
concentrating the above mixed solution to half of the original volume (about 20mL) at 45 ℃;
slowly cooling to 1 ℃, then slowly adding n-hexane until turbidity appears, and stirring for 2 hours under heat preservation to crystallize;
filtering, collecting precipitated crystals, and vacuum drying at 50 ℃ to obtain 0.87g of tedizolid phosphate crystal with the HPLC purity of 99.95%; DSC showed a melting point of 235 ℃.
The tedizolid phosphate crystal obtained in the embodiment still has the XRD spectrum characteristics shown in figure 1, the DSC spectrum characteristics shown in figure 2 and the TGA spectrum characteristics shown in figure 3.
Example 6
Dissolving 10g of tedizolid phosphate raw material in a mixed solvent formed by 200mL of N, N-dimethylformamide and 200mL of water at 80 ℃ to obtain a colorless to light yellow mixed solution;
naturally cooling the solution to 55 ℃, preserving heat, stirring for 1 hour, and then naturally cooling to 5 ℃ while stirring;
filtering, collecting crystals, and vacuum drying at 60 deg.C to obtain tedizolid phosphate crystal 9.3g with HPLC purity of 99.90%; DSC showed a melting point of 235 ℃.
The tedizolid phosphate crystal obtained in the embodiment still has the XRD spectrum characteristics shown in figure 1, the DSC spectrum characteristics shown in figure 2 and the TGA spectrum characteristics shown in figure 3.
Example 7
Dissolving 10g of tedizolid phosphate raw material in a mixed solvent formed by 400mL of N, N-dimethylformamide and 100mL of water at 60 ℃ to obtain a colorless to light yellow mixed solution;
naturally cooling the solution to 50 ℃, preserving heat, stirring for 1 hour, and then naturally cooling to 3 ℃ while stirring;
filtering, collecting crystals, and vacuum drying at 60 deg.C to obtain tedizolid phosphate crystal 9.1g with HPLC purity of 99.91%; DSC showed a melting point of 235 ℃.
The tedizolid phosphate crystal obtained in the embodiment still has the XRD spectrum characteristics shown in figure 1, the DSC spectrum characteristics shown in figure 2 and the TGA spectrum characteristics shown in figure 3.
Example 8
Dissolving 10g of tedizolid phosphate raw material in a mixed solvent formed by 600mL of N, N-dimethylformamide and 100mL of water at 50 ℃ to obtain a colorless to light yellow mixed solution;
naturally cooling the solution to 45 ℃, preserving heat, stirring for 1 hour, and then naturally cooling to 6 ℃ while stirring;
filtering, collecting crystals, and vacuum drying at 60 deg.C to obtain tedizolid phosphate crystal 9.5g with HPLC purity of 99.88%; DSC showed a melting point of 235 ℃.
The tedizolid phosphate crystal obtained in the embodiment still has the XRD spectrum characteristics shown in figure 1, the DSC spectrum characteristics shown in figure 2 and the TGA spectrum characteristics shown in figure 3.
Example 9
Firstly, dissolving 1g of tedizolid phosphate disodium salt in a mixed solvent formed by 20mL of water and 2mL of N, N-dimethylformamide at room temperature, acidifying (adding hydrochloric acid to adjust the pH value of the solution to be 1.5), supplementing 18mL of N, N-dimethylformamide, and heating to 80 ℃ to obtain a colorless-light yellow mixed solution;
naturally cooling the solution to 55 ℃, preserving heat, stirring for 1 hour, and then naturally cooling to 6 ℃ while stirring;
filtering, collecting crystals, and vacuum drying at 60 deg.C to obtain tedizolid phosphate crystal 9.4g with HPLC purity of 99.85%; DSC showed a melting point of 235 ℃.
The tedizolid phosphate crystal obtained in the embodiment still has the XRD spectrum characteristics shown in figure 1, the DSC spectrum characteristics shown in figure 2 and the TGA spectrum characteristics shown in figure 3.
Example 10
Firstly, dissolving 1g of tedizolid phosphate disodium salt in a mixed solvent formed by 10mL of water and 2mL of N, N-dimethylformamide at room temperature, acidifying (adding hydrochloric acid to adjust the pH value of the solution to be 2.5), supplementing 38mL of N, N-dimethylformamide, and heating to 60 ℃ to obtain a colorless to light yellow mixed solution;
naturally cooling the solution to 45 ℃, preserving heat, stirring for 1 hour, and then naturally cooling to 3 ℃ while stirring;
filtering, collecting crystals, and vacuum drying at 60 deg.C to obtain tedizolid phosphate crystal 9.5g with HPLC purity of 99.89%; DSC showed a melting point of 235 ℃.
The tedizolid phosphate crystal obtained in the embodiment still has the XRD spectrum characteristics shown in figure 1, the DSC spectrum characteristics shown in figure 2 and the TGA spectrum characteristics shown in figure 3.
Comparative example 1
Tedizolid phosphate crystal form I is prepared by referring to example 1 in WO2010091131A 1.
The X-ray powder diffraction pattern of the obtained crystal is shown in FIG. 4, and can be seen by comparing FIG. 1 with FIG. 4: the tedizolid phosphate crystal has obvious difference with the crystal form I in diffraction peak position and relative intensity, such as: the tedizolid phosphate crystal has main characteristic peaks (peaks with relative strength of more than or equal to 20 percent) at diffraction angles of 11.9 degrees, 13.8 degrees, 14.8 degrees, 15.4 degrees, 15.6 degrees, 16.3 degrees, 17.1 degrees, 20.7 degrees, 20.9 degrees, 22.0 degrees, 23.8 degrees, 24.5 degrees and 27.5 degrees, and the characteristic peak with the relative strength of 100 percent is 16.3 degrees at 2 theta; the crystal form I has main characteristic peaks (peaks with relative intensity being more than or equal to 20 percent) at diffraction angles 2 theta of 14.7 degrees, 15.2 degrees, 15.4 degrees, 16.6 degrees, 20.3 degrees, 21.4 degrees, 22.4 degrees, 24.7 degrees, 26.8 degrees, 28.2 degrees and 28.4 degrees, and the characteristic peak with the relative intensity being 100 percent is 20.3 degrees at 2 theta; the crystal of tedizolid phosphate of the invention is obviously different from the crystal form I and is different.
Comparative example 2
Tedizolid phosphate crystal form II is prepared by referring to example 1 in WO2015158202A 1.
The X-ray powder diffraction pattern of the obtained crystal is shown in FIG. 5, and can be seen by comparing FIG. 1 with FIG. 5: the diffraction peak positions and relative intensities of the tedizolid phosphate crystal disclosed by the invention and the crystal form II have obvious differences, such as: the novel crystal form of the invention has some characteristic peaks (such as 10.9, 14.8, 15.4, 19.1, 20.7, 22.0 and 22.9) which are not possessed by the crystal form II; in addition, the tedizolid phosphate crystal has main characteristic peaks (peaks with relative strength of more than or equal to 20 percent) at diffraction angles of 11.9 degrees, 13.8 degrees, 14.8 degrees, 15.4 degrees, 15.6 degrees, 16.3 degrees, 17.1 degrees, 20.7 degrees, 20.9 degrees, 22.0 degrees, 23.8 degrees, 24.5 degrees and 27.5 degrees, and the characteristic peak with the relative strength of 100 percent is 16.3 degrees at 2 theta; the crystal form II has main characteristic peaks (peaks with relative intensity being more than or equal to 20%) at diffraction angles 2 theta of 10.5 degrees, 15.7 degrees, 21.0 degrees and 26.3 degrees, and the characteristic peak with the relative intensity being 100% is 15.7 degrees at 2 theta; the crystal of tedizolid phosphate of the invention is obviously different from the crystal form II and is different.
Stability test
The following stability comparison experiment was performed on the tedizolid phosphate crystal of the present invention, the crystal form i crystal of comparative example 1, and the crystal form ii crystal of comparative example 2.
The crystal samples were treated as follows:
standing at 25 deg.C with relative humidity of 92.5% for 1 month;
standing at 60 deg.C under illumination intensity of 6000lx for 1 month;
samples were taken after 1 month period for XRD and HPLC analysis, respectively.
XRD analysis results show that: the crystal is not subjected to crystal form change after the high-temperature treatment, the high-temperature treatment and the illumination treatment.
Table 4 shows the HPLC purity measurements.
TABLE 4 HPLC purity test results
As can be seen from the results of table 4: the crystal form I has poor stability under high-temperature (60 ℃) illumination (illumination intensity of 6000lx), the maximum single impurity content is changed from 0.10% to 0.41%, and the maximum single impurity content is increased by 3.1 times; although the stability of the crystal form II under high-temperature (60 ℃) illumination (illumination intensity 6000lx) is good, the maximum single impurity content is only changed from 0.12% to 0.15%, the stability of the crystal form II under high humidity (relative humidity is 92.5% and 25 ℃) is poor, the maximum single impurity content is changed from 0.12% to 0.48%, and the increase is 3 times; the tedizolid phosphate crystal disclosed by the invention has very high stability under high-humidity and high-temperature illumination, and the maximum single impurity content is less than 0.1%, so that the tedizolid phosphate crystal disclosed by the invention is obviously superior to the existing crystal form I crystal and crystal form II crystal in stability under high-humidity, heat and illumination, and is very beneficial to quality control of subsequent preparations.
Solubility test
Respectively taking 20.0mg of the crystal form I crystal in the comparative example 1, the crystal form II crystal in the comparative example 2 and the tedizolid phosphate crystal, respectively adding 100mL of water, stirring for 10 hours at 25 ℃, respectively centrifuging, filtering, taking supernate, and performing HPLC content determination, wherein the test result is as follows: the solubility of the crystal form I in water is only 0.10mg/mL, the solubility of the crystal form II in water is slightly improved to 0.16mg/mL, and the solubility of the tedizolid phosphate crystal in water is obviously improved to 0.80 mg/mL.
In summary, it can be seen that: the tedizolid phosphate crystal provided by the invention has high stability under high humidity, heat and illumination, has remarkably improved solubility in water, is very suitable for application and production of pharmaceutical preparations, and has obvious industrial application value.
It is finally necessary to point out here: the above examples are only for further illustration of the technical solutions of the present invention, and should not be understood as limiting the scope of the present invention, and the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above descriptions are within the scope of the present invention.
Claims (9)
1. The tedizolid phosphate crystal is characterized in that: under X-ray powder diffraction, main characteristic peaks exist at diffraction angles 2 theta of 11.9 degrees, 13.8 degrees, 14.8 degrees, 15.4 degrees, 15.6 degrees, 16.3 degrees, 17.1 degrees, 20.7 degrees, 20.9 degrees, 22.0 degrees, 23.8 degrees, 24.5 degrees and 27.5 degrees, and the test error is +/-0.2 degrees; the main characteristic peak is a peak with the relative intensity of more than or equal to 20 percent.
2. The tedizolid phosphate crystal of claim 1, wherein: under X-ray powder diffraction, characteristic peaks exist at diffraction angles 2 theta of 10.4, 10.9, 11.9 degrees, 13.8 degrees, 14.8 degrees, 15.4 degrees, 15.6 degrees, 16.3 degrees, 17.1 degrees, 17.7 degrees, 19.1 degrees, 20.0 degrees, 20.7 degrees, 20.9 degrees, 21.3 degrees, 22.0 degrees, 22.9 degrees, 23.8 degrees, 24.5 degrees, 26.3 degrees, 27.5 degrees, 28.8 degrees and 33.9 degrees, and the test error is +/-0.2 degrees; the characteristic peak refers to the peak with relative intensity of more than 5%.
3. A method for preparing tedizolid phosphate crystal of claim 1 or 2, comprising the steps of:
a) concentrating a mixed solution formed by tedizolid phosphate, an organic solvent and water at the temperature of 30-50 ℃ to 1/3-2/3 of the original volume; the organic solvent is selected from any one of methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone and ethyl acetate; the volume ratio of the organic solvent to the water is 100: 1-1: 1; the content of tedizolid phosphate in the mixed solution is 0.01-1.0 g/mL;
b) cooling to 0-10 ℃, dropwise adding an anti-solvent into the mixed solution concentrated in the step a) until the mixed solution is turbid, and stirring for 1-3 hours while keeping the temperature; the anti-solvent is selected from any one of methyl tert-butyl ether, isopropyl ether, n-hexane, cyclopentane and n-pentane;
c) and filtering, collecting precipitated crystals, and drying at 40-90 ℃ to obtain the tedizolid phosphate crystal.
4. The method of claim 3, wherein: the mixed solution in the step a) is prepared by directly dissolving tedizolid phosphate raw material in an organic solvent and water at the volume ratio of 100: 1-1: 1 in a mixed solvent.
5. The method of claim 3, wherein: the mixed solution in the step a) is prepared by dissolving tedizolid phosphate disodium salt in water and the organic solvent according to the volume ratio of 50: 1-1: 1, adding the same organic solvent after acidification until the volume ratio of the organic solvent to water in the system is 100: 1-1: 1 to obtain the compound.
6. A method for preparing tedizolid phosphate crystal of claim 1 or 2, comprising the steps of:
A) completely dissolving the tedizolid phosphate raw material in a solvent at the temperature of 30-100 ℃; the solvent is an organic solvent and water according to the volume ratio of 100: 1-1: 10 to form a mixed solvent; the organic solvent is an organic amine solvent or an amide solvent;
B) naturally cooling the solution obtained in the step A to 40-60 ℃, and stirring for 1-3 hours while keeping the temperature; then naturally cooling to 0-10 ℃ while stirring;
C) and filtering, collecting precipitated crystals, and drying at 40-90 ℃ to obtain the tedizolid phosphate crystal.
7. A method for preparing tedizolid phosphate crystal of claim 1 or 2, comprising the steps of:
at the temperature of 20-40 ℃, the tedizolid phosphate disodium salt is completely dissolved in an organic solvent and water according to the volume ratio of 100: 1-1: 100 in a mixed solvent; the organic solvent is an organic amine solvent or an amide solvent;
secondly, acidifying the solution obtained in the step one to ensure that the pH of the solution is 0.5-4;
supplementing the organic solvent which is the same as the organic solvent in the step I, and enabling the volume ratio of the organic solvent to water in the solution system to be 100: 1-1: 100, and then heating to 60-80 ℃ to obtain a clear solution;
fourthly, naturally cooling the solution obtained in the third step to 40-60 ℃, preserving heat and stirring for 1-3 hours; then naturally cooling to 0-10 ℃ while stirring;
fifthly, filtering and collecting precipitated crystals, and drying at 40-90 ℃ to obtain the tedizolid phosphate crystal.
8. The method of claim 4 or 6, wherein: the tedizolid phosphate raw material is in any known form.
9. The method of claim 5 or 7, wherein: the tedizolid phosphate disodium salt is in any known form.
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| CN101982468A (en) * | 2003-12-18 | 2011-03-02 | 东亚制药株式会社 | Novel oxazolidinone derivatives and pharmaceutical compositions comprising the derivatives |
| CN104327119A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tedizolid phosphate |
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| MX2011008093A (en) * | 2009-02-03 | 2011-11-29 | Trius Therapeutics | Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-y l)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate. |
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| CN104327119A (en) * | 2014-10-17 | 2015-02-04 | 苏州明锐医药科技有限公司 | Preparation method of tedizolid phosphate |
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