CN105837634A - Tedizolid phosphate crystal and preparation method thereof - Google Patents
Tedizolid phosphate crystal and preparation method thereof Download PDFInfo
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- CN105837634A CN105837634A CN201610051458.9A CN201610051458A CN105837634A CN 105837634 A CN105837634 A CN 105837634A CN 201610051458 A CN201610051458 A CN 201610051458A CN 105837634 A CN105837634 A CN 105837634A
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- Prior art keywords
- phosphate ester
- azoles amine
- safe ground
- solvent
- ground azoles
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- 239000013078 crystal Substances 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 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 abstract description 6
- 229960003947 tedizolid phosphate Drugs 0.000 title abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 21
- 238000012360 testing method Methods 0.000 claims abstract description 8
- -1 azoles amine phosphate ester Chemical class 0.000 claims description 96
- 229910019142 PO4 Inorganic materials 0.000 claims description 84
- 239000010452 phosphate Substances 0.000 claims description 84
- 239000007787 solid Substances 0.000 claims description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 42
- 239000003960 organic solvent Substances 0.000 claims description 28
- 239000011259 mixed solution Substances 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 14
- 239000002994 raw material Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 11
- 238000001556 precipitation Methods 0.000 claims description 11
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012296 anti-solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 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
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- 238000005286 illumination Methods 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 238000002411 thermogravimetry Methods 0.000 description 14
- 238000002441 X-ray diffraction Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000010583 slow cooling Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 150000003851 azoles Chemical class 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 230000003750 conditioning effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004455 differential thermal analysis Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- UYGKMSUDBLULNG-UHFFFAOYSA-N 3-[(2-oxo-1,3-oxazolidin-5-yl)methyl]thiophene-2-carboxamide Chemical class S1C=CC(CC2OC(=O)NC2)=C1C(=O)N UYGKMSUDBLULNG-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- 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. Under X-ray powder diffraction, the tedizolid phosphate 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. A test error is +/-0.2 degrees. The main characteristic peaks have relative intensity greater than or equal to 20%. An experiment proves that the tedizolid phosphate crystal has high stability under conditions of high humidity, heat and illumination, substantially improves dissolvability in water, is very suitable for medicinal preparation application and production and has obvious industrial application value.
Description
Technical field
The present invention relates to a kind of safe ground azoles amine phosphate ester crystalline solid and preparation method thereof, belongs to field of pharmaceutical chemistry technology.
Background technology
Safe ground azoles amine phosphate ester (Tedizolid Phosphate) is a kind of second filial generation (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic, in 2014
Within 06 month 20 days, obtain FDA listing approval.The chemistry of safe ground azoles amine phosphate ester is entitled: (R)-3-(4-(2-(2-methyl tetrazolium-5-base)
Pyridine-5-base)-3-fluorophenyl)-5-methylol oxazolidine-2-ketone dihydrogen phosphoric acid ester, molecular formula is: C17H16FN6O6P, molecular weight
Being 450.32, No. CAS is 856867-55-5, and its structural formula is:
Safe ground azoles amine phosphate ester and safe ground azoles amine disodium phosphate is disclosed in international patent documents WO2005058886A1
The preparation method of salt, but do not show the crystallization or purification that they can be stable.
A kind of safe ground azoles amine phosphate ester crystalline solid is disclosed (in prior art in international patent documents WO2010091131A1
It is referred to as crystal formation I), it has an X-ray powder diffraction data shown in table 1:
DSC shows that the fusing point of this crystalline solid is about 255～258 DEG C (256.9 DEG C).Although experiment shows that this crystalline solid is more steady
Fixed, not there is hygroscopicity, but this crystalline solid easily forms microgranule, so that filtration treatment is more difficult；Especially, described crystallization
Body dissolubility in water only has 0.1mg/mL, and water solublity is the poorest, is unfavorable for absorption of human body.
In order to solve the problem of safe ground azoles amine phosphate ester poorly water-soluble, WO2015158202A1 discloses a kind of safe ground azoles amine phosphorus
Acid esters crystalline solid (referred to herein as crystal formation II), it has an X-ray powder diffraction data shown in table 2:
And to disclose this crystalline solid (crystal formation II) dissolubility in water in the text be 168 μ g/mL, and crystal formation I is in water
Dissolubility is only 118 μ g/mL.Although the dissolubility that crystal formation II is in water increases relative to crystal formation I, but improving is not very
Substantially, however it remains poorly water-soluble, the problem being unfavorable for absorption of human body and utilization.
Summary of the invention
The problems referred to above existed for prior art, it is desirable to provide a kind of have good dissolubility, heat stability,
Safe ground azoles amine phosphate ester crystalline solid of high humidity stability and pressure stability and preparation method thereof, with meet follow-up formulation development and
Large-scale production requirement.
Safe ground provided by the present invention azoles amine phosphate ester crystalline solid, under X-ray powder diffraction, angle of diffraction 2 θ be 11.9 °,
13.8 °, 14.8 °, 15.4 °, 15.6 °, 16.3 °, 17.1 °, 20.7 °, 20.9 °, 22.0 °, 23.8 °, 24.5 °, have at 27.5 °
Main characteristic peak, test error is ± 0.2 °.
Furtherly, safe ground of the present invention azoles amine phosphate ester crystalline solid, under X-ray powder diffraction, in angle of diffraction
2 θ are 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 °, there is characteristic peak, test error at 28.8,33.9
For ± 0.2 °.
Furtherly, safe ground of the present invention azoles amine phosphate ester crystalline solid, there is the X-ray powder diffraction shown in Fig. 1
Spectrogram, characteristic peak data therein are as shown in table 3:
Heretofore described " main characteristic peak " refers to the peak of relative intensity >=20%.
Heretofore described " characteristic peak " refers to the peak of relative intensity ＞ 5%.
A kind of method preparing safe ground of the present invention azoles amine phosphate ester crystalline solid, comprises the steps:
A) at 30～50 DEG C (preferably 40～45 DEG C), to the mixing formed with organic solvent and water by safe ground azoles amine phosphate ester
Solution is concentrated into 1/3～2/3 (preferably 1/2) of original volume；Described organic solvent is selected from methanol, ethanol, acetone, second
Any one in nitrile, oxolane, N,N-dimethylformamide, N-Methyl pyrrolidone, ethyl acetate, thionyl chloride is (excellent
Elect oxolane, N,N-dimethylformamide or thionyl chloride as)；Organic solvent is 100:1～1:1 with the volume ratio of water
(preferably 60:1～1:1)；Safe ground azoles amine phosphate ester content in mixed solution is 0.01～1.0g/mL；
B) being cooled to 0～10 DEG C, the mixed solution and dripping anti-solvent after concentrating through step a) is to there is muddiness, and insulation is stirred
Mix 1～3 hour；Described anti-solvent appointing in methyl tertiary butyl ether(MTBE), diisopropyl ether, normal hexane, Pentamethylene., pentane
A kind of (preferably normal hexane)；
C) crystal of precipitation is collected by filtration, at 40～90 DEG C, is dried (being preferably vacuum dried at 50～60 DEG C), to obtain final product
Described safe ground azoles amine phosphate ester crystalline solid.
Mixed solution described in step a) can be straight at 10～100 DEG C (preferably 30～60 DEG C) by safe ground azoles amine phosphate ester raw material
Connect to be dissolved in and formed for 100:1～1:1 (preferably 60:1～1:1) by volume by described organic solvent and water
Mixed solvent obtains；Also can be first molten under 10～100 DEG C (preferably 20～60 DEG C) by safe ground azoles amine organic phosphate disodium salt
Xie Yu is, in the mixed solvent that 50:1～1:1 is formed, to mend after being acidified by water and described organic solvent by volume again
Adding identical organic solvent to the volume ratio of the organic solvent in system with water is that 100:1～1:1 obtains.
The another kind of method preparing safe ground of the present invention azoles amine phosphate ester crystalline solid, comprises the steps:
A) at 30～100 DEG C (preferably 50～80 DEG C), safe ground azoles amine phosphate ester raw material is made to be dissolved completely in solvent；Institute
Stating solvent is that organic solvent or organic solvent are formed for 100:1～1:10 (preferably 10:1～1:1) by volume with water
Mixed solvent；Described organic solvent is organic amine solvent or amide solvent, include but not limited to DMF,
DMAC N,N' dimethyl acetamide, pyridine (preferably N,N-dimethylformamide)；
B) making the solution Temperature fall to 40～60 DEG C (preferably 45～55 DEG C) that step A obtains, insulated and stirred 1～3 is little
Time；Temperature fall to 0～10 DEG C (preferably 1～6 DEG C) the most while stirring；
C) crystal of precipitation is collected by filtration, at 40～90 DEG C, is dried (being preferably vacuum dried at 50～60 DEG C), to obtain final product
Described safe ground azoles amine phosphate ester crystalline solid.
Another prepares the method for safe ground of the present invention azoles amine phosphate ester crystalline solid, comprises the steps:
1. at 20～40 DEG C, making safe ground azoles amine organic phosphate disodium salt be dissolved completely in organic solvent with water is 100 by volume:
In the mixed solvent that 1～1:100 (preferably 1:5～1:10) is formed；Described organic solvent is organic amine solvent or acyl
Amine solvent, includes but not limited to DMF, N,N-dimethylacetamide, pyridine (preferably N, N-diformazan
Base Methanamide)；
2. the solution 1. obtained step is acidified, and the pH making solution is 0.5～4 (preferably 1.5～2.5)；
3. add the organic solvent the most identical with step, make the volume ratio of organic solvent in solution system and water be 100:1～
1:100 (preferably 2:1～4:1), is then heated to 60～80 DEG C, obtains settled solution；
4. making the solution Temperature fall to 40～60 DEG C (preferably 45～55 DEG C) that 3. step obtains, insulated and stirred 1～3 is little
Time；Temperature fall to 0～10 DEG C (preferably 1～6 DEG C) the most while stirring；
5. the crystal of precipitation is collected by filtration, at 40～90 DEG C, is dried (being preferably vacuum dried at 50～60 DEG C), to obtain final product
Described safe ground azoles amine phosphate ester crystalline solid.
Described safe ground azoles amine phosphate ester raw material and safe ground azoles amine organic phosphate disodium salt are known any kenel.
Experiment proves: the kenel of the safe ground azoles amine phosphate ester crystalline solid that the present invention provides is stable, easily filters separation, and purity is high,
Steady quality, not only has heat stability, high humidity stability and pressure stability, and the dissolubility in water is by existing skill
The 0.1mg/mL of art brings up to 0.8mg/mL；And preparation technology is simple, it is easy to operation and scale, follow-up system
The exploitation of agent and large-scale production, have industrial application value.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRD) spectrogram of the safe ground azoles amine phosphate ester crystalline solid that the present invention obtains；
Fig. 2 is differential thermal analysis (DSC) spectrogram of the safe ground azoles amine phosphate ester crystalline solid that the present invention obtains；
Fig. 3 is thermogravimetric analysis (TGA) spectrogram of the safe ground azoles amine phosphate ester crystalline solid that the present invention obtains；
Fig. 4 is the X-ray powder on safe ground azoles amine phosphate ester crystalline solid (known in the prior art as crystal formation I) that comparative example 1 prepares
End diffraction (XRD) spectrogram.
Fig. 5 is the X-ray powder on safe ground azoles amine phosphate ester crystalline solid (known in the prior art as crystal formation II) that comparative example 2 prepares
End diffraction (XRD) spectrogram.
Detailed description of the invention
With embodiment, technical scheme is described in further detail below in conjunction with the accompanying drawings.
Safe ground azoles amine phosphate ester raw material used in embodiment and safe ground azoles amine organic phosphate disodium salt are to respectively refer to Chinese patent
Described in CN102439006A embodiment 1-9 and patent CN102177156A embodiment 8, method prepares.
X-ray powder diffraction (XRD) spectrogram that the present invention obtains is to have 1.5460 angstromsWavelength α1、1.54439
AngstromWavelength α2Radiation source, strength ratio α1/α2Be 0.5,40kV voltage and the Dedye of 30mA current intensity～
Scherrer INEL CPS～120 equipment measure analysis obtain.It will be appreciated by those skilled in the art that X-ray powder diffraction
Analyzing and depend on used measuring condition, under different measuring conditions, obtained X-ray powder diffraction spectrum is likely to be of
Certain measurement error.Especially, the intensity in usual X-ray powder diffraction spectrum may be along with the difference of test condition
And fluctuated.Will be further understood that relative intensity is likely to change with the difference of experiment condition, therefore, do not take an examination
Consider the exact numerical of intensity.Additionally, for conventional X-ray powder diagram, the measurement error of the angle of diffraction typical about 5%
Or less, for the above-mentioned angle of diffraction, it is considered as the measurement error of such degree.
Differential thermal analysis (DSC) spectrogram that the present invention obtains is in hermetic container, is passed through 50mL/min nitrogen stream, in 20～450
At a temperature of between DEG C, the rate of heat addition is 10 DEG C/min, measures analysis and obtain in DSC Q 2000 (TA company of the U.S.) equipment.
Thermogravimetric analysis (TGA) spectrogram that the present invention obtains is to be analyzed obtaining on TA instrument TGA2050, described calibration mark
Quasi-sample is nickel and nickel alumin(i)um alloy；Sample is with the speed heating of 10 DEG C/min in nitrogen, and rising to final temperature is 300 DEG C.
The condition that the present invention carries out HPLC purity test analysis is as follows:
Embodiment 1
1.0g Thailand ground azoles amine phosphate ester raw material is made to be dissolved at 60 DEG C by 30mL N,N-dimethylformamide and 0.5mL water shape
In the mixed solvent become, obtain colourless to faint yellow mixed solution；
Half (about 15mL) at 45 DEG C of above-mentioned mixed solutions of concentration to original volume；
Slow cooling, to 1 DEG C, is then slowly added into normal hexane to muddiness occur, and insulated and stirred makes crystallize in 2 hours；
The crystal of precipitation is collected by filtration, in 50 DEG C of vacuum drying, obtains described safe ground azoles amine phosphate ester crystalline solid 0.9g, HPLC
Purity is 99.90%；DSC display fusing point is 234 DEG C.
The XRD spectra of the safe ground azoles amine phosphate ester crystalline solid that Fig. 1 is obtained by the present invention, as seen from Figure 1: described crystalline solid
Under X-ray powder diffraction, the angle of diffraction 2 θ be 11.9 °, 13.8 °, 14.8 °, 15.4 °, 15.6 °, 16.3 °, 17.1 °,
20.7 °, 20.9 °, 22.0 °, 23.8 °, 24.5 °, there is main characteristic peak at 27.5 °；Angle of diffraction 2 θ be 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 °, there is characteristic peak at 28.8,33.9, test error is ± 0.2 °；Its
In characteristic peak data specific as follows shown in:
The DSC spectrogram of the safe ground azoles amine phosphate ester crystalline solid that Fig. 2 is obtained by the present invention, as seen from Figure 2: of the present invention
Crystalline solid has melted endothermic peak at 230～237 DEG C (specially 235.1 DEG C).
The TGA spectrogram of the safe ground azoles amine phosphate ester crystalline solid that Fig. 3 is obtained by the present invention, as seen from Figure 3: of the present invention
Crystalline solid is anhydride.
Embodiment 2
1.0g Thailand ground azoles amine phosphate ester raw material is made to be dissolved in the mixing formed by 50mL oxolane and 50mL water at 50 DEG C
In solvent, obtain faint yellow mixed solution；
Half (about 50mL) at 40 DEG C of above-mentioned mixed solutions of concentration to original volume；
Slow cooling, to 10 DEG C, is then slowly added into normal hexane to muddiness occur, and insulated and stirred makes crystallize in 2 hours；
The crystal of precipitation is collected by filtration, in 50 DEG C of vacuum drying, obtains described safe ground azoles amine phosphate ester crystalline solid 0.89g,
HPLC purity is 99.7%；DSC display fusing point is 236 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid also has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Embodiment 3
1.0g Thailand ground azoles amine phosphate ester raw material is made to be dissolved in the mixing formed by 10mL thionyl chloride and 0.2mL water at 45 DEG C
In solvent, obtain faint yellow mixed solution；
Half (about 5mL) at 40 DEG C of above-mentioned mixed solutions of concentration to original volume；
Slow cooling, to 5 DEG C, is then slowly added into normal hexane to muddiness occur, and insulated and stirred makes crystallize in 2 hours；
The crystal of precipitation is collected by filtration, in 50 DEG C of vacuum drying, obtains described safe ground azoles amine phosphate ester crystalline solid 0.91g,
HPLC purity is 99.75%；DSC display fusing point is 233 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid also has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Embodiment 4
1.0g Thailand ground azoles amine phosphate ester raw material is made to be dissolved at 30 DEG C by 60mL N,N-dimethylformamide and 5mL water shape
In the mixed solvent become, obtain faint yellow mixed solution；
Half (about 32mL) at 45 DEG C of above-mentioned mixed solutions of concentration to original volume；
Slow cooling, to 1 DEG C, is then slowly added into normal hexane to muddiness occur, and insulated and stirred makes crystallize in 2 hours；
The crystal of precipitation is collected by filtration, in 50 DEG C of vacuum drying, obtains described safe ground azoles amine phosphate ester crystalline solid 0.84g,
HPLC purity is 99.79%；DSC display fusing point is 234 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid also has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Embodiment 5
First 1g Thailand ground azoles amine organic phosphate disodium salt is made to be dissolved at room temperature by 10mL water and 4mL N, N-dimethyl formyl
In the mixed solvent that amine is formed, after acidifying (pH adding hydrochloric acid conditioning solution is 2.5), add DMF
15mL, is heated to 80 DEG C, obtains colourless to faint yellow mixed solution；
Half (about 20mL) at 45 DEG C of above-mentioned mixed solutions of concentration to original volume；
Slow cooling, to 1 DEG C, is then slowly added into normal hexane to muddiness occur, and insulated and stirred makes crystallize in 2 hours；
The crystal of precipitation is collected by filtration, in 50 DEG C of vacuum drying, obtains described safe ground azoles amine phosphate ester crystalline solid 0.87g,
HPLC purity is 99.95%；DSC display fusing point is 235 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid still has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Embodiment 6
10g Thailand ground azoles amine phosphate ester raw material is made to be dissolved at 80 DEG C by 200mL N,N-dimethylformamide and 200mL water
In the mixed solvent formed, obtain colourless to faint yellow mixed solution；
Above-mentioned solution is made to be naturally cooling to 55 DEG C, insulated and stirred 1 hour, it is naturally cooling to 5 DEG C the most while stirring；
Crystal is collected by filtration, in 60 DEG C of vacuum drying, i.e. obtains described safe ground azoles amine phosphate ester crystalline solid 9.3g, HPLC
Purity is 99.90%；DSC display fusing point is 235 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid still has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Embodiment 7
10g Thailand ground azoles amine phosphate ester raw material is made to be dissolved at 60 DEG C by 400mL N,N-dimethylformamide and 100mL water
In the mixed solvent formed, obtain colourless to faint yellow mixed solution；
Above-mentioned solution is made to be naturally cooling to 50 DEG C, insulated and stirred 1 hour, it is naturally cooling to 3 DEG C the most while stirring；
Crystal is collected by filtration, in 60 DEG C of vacuum drying, i.e. obtains described safe ground azoles amine phosphate ester crystalline solid 9.1g, HPLC
Purity is 99.91%；DSC display fusing point is 235 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid still has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Embodiment 8
10g Thailand ground azoles amine phosphate ester raw material is made to be dissolved at 50 DEG C by 600mL N,N-dimethylformamide and 100mL water
In the mixed solvent formed, obtain colourless to faint yellow mixed solution；
Above-mentioned solution is made to be naturally cooling to 45 DEG C, insulated and stirred 1 hour, it is naturally cooling to 6 DEG C the most while stirring；
Crystal is collected by filtration, in 60 DEG C of vacuum drying, i.e. obtains described safe ground azoles amine phosphate ester crystalline solid 9.5g, HPLC
Purity is 99.88%；DSC display fusing point is 235 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid still has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Embodiment 9
First 1g Thailand ground azoles amine organic phosphate disodium salt is made at room temperature to be dissolved in by 20mL water and 2mL N, N-dimethyl formyl
In the mixed solvent that amine is formed, after acidifying (pH adding hydrochloric acid conditioning solution is 1.5), add DMF
18mL, is then heated to 80 DEG C, obtains colourless to faint yellow mixed solution；
Above-mentioned solution is made to be naturally cooling to 55 DEG C, insulated and stirred 1 hour, it is naturally cooling to 6 DEG C the most while stirring；
Crystal is collected by filtration, in 60 DEG C of vacuum drying, i.e. obtains described safe ground azoles amine phosphate ester crystalline solid 9.4g, HPLC
Purity is 99.85%；DSC display fusing point is 235 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid still has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Embodiment 10
First 1g Thailand ground azoles amine organic phosphate disodium salt is made at room temperature to be dissolved in by 10mL water and 2mL N, N-dimethyl formyl
In the mixed solvent that amine is formed, after acidifying (pH adding hydrochloric acid conditioning solution is 2.5), add DMF
38mL, is heated to 60 DEG C, obtains colourless to faint yellow mixed solution；
Above-mentioned solution is made to be naturally cooling to 45 DEG C, insulated and stirred 1 hour, it is naturally cooling to 3 DEG C the most while stirring；
Crystal is collected by filtration, in 60 DEG C of vacuum drying, i.e. obtains described safe ground azoles amine phosphate ester crystalline solid 9.5g, HPLC
Purity is 99.89%；DSC display fusing point is 235 DEG C.
The present embodiment gained Thailand ground azoles amine phosphate ester crystalline solid still has shown in the XRD spectra feature shown in Fig. 1 and Fig. 2
TGA chromatogram characteristic shown in DSC chromatogram characteristic and Fig. 3.
Comparative example 1
Safe ground azoles amine phosphate ester crystal formation I crystal is prepared with reference to embodiment in WO2010091131A1 1.
As shown in Figure 4, comparison diagram 1 and Fig. 4 is visible for the X-ray powder diffraction spectrum of gained crystal: the safe ground azoles of the present invention
Amine phosphate ester crystalline solid has notable difference, such as with diffraction maximum position and the relative intensity of crystal formation I crystal: the Thailand of the present invention
Ground azoles amine phosphate ester crystalline solid the angle of diffraction 2 θ be 11.9 °, 13.8 °, 14.8 °, 15.4 °, 15.6 °, 16.3 °, 17.1 °, 20.7 °,
20.9 °, 22.0 °, 23.8 °, 24.5 °, there is main characteristic peak (peak of relative intensity >=20%) at 27.5 °, relative intensity is 100%
Characteristic peak be 16.3 ° at 2 θ；And crystal formation I crystal the angle of diffraction 2 θ be 14.7 °, 15.2 °, 15.4 °, 16.6 °, 20.3 °,
21.4 °, 22.4 °, 24.7 °, 26.8 °, 28.2 °, there is main characteristic peak (peak of relative intensity >=20%) at 28.4 °, relatively strong
Degree be the characteristic peak of 100% be 20.3 ° at 2 θ；Illustrate that the safe ground azoles amine phosphate ester crystalline solid of the present invention has substantially with crystal formation I
Difference, is different crystalline solid.
Comparative example 2
Safe ground azoles amine phosphate ester crystal formation II crystal is prepared with reference to embodiment in WO2015158202A1 1.
The X-ray powder diffraction spectrum of gained crystal is as it is shown in figure 5, comparison diagram 1 and Fig. 5 is visible: the safe ground azoles of the present invention
Amine phosphate ester crystalline solid has notable difference, such as with diffraction maximum position and the relative intensity of crystal formation II crystal: the present invention's is new
Crystal formation has some unexistent characteristic peaks of crystal formation II (such as 10.9,14.8,15.4,19.1,20.7,22.0,22.9)；It addition,
The safe ground azoles amine phosphate ester crystalline solid of the present invention the angle of diffraction 2 θ be 11.9 °, 13.8 °, 14.8 °, 15.4 °, 15.6 °, 16.3 °,
17.1 °, 20.7 °, 20.9 °, 22.0 °, 23.8 °, 24.5 °, there is main characteristic peak (peak of relative intensity >=20%) at 27.5 °,
Relative intensity be the characteristic peak of 100% be 16.3 ° at 2 θ；And crystal formation II crystal the angle of diffraction 2 θ be 10.5 °, 15.7 °, 21.0 °,
There is at 26.3 ° main characteristic peak (peak of relative intensity >=20%), relative intensity be the characteristic peak of 100% be 15.7 ° at 2 θ；
Illustrate that the safe ground azoles amine phosphate ester crystalline solid of the present invention has notable difference with crystal formation II, be different crystalline solid.
Stability test
Safe ground azoles amine phosphate ester crystalline solid, crystal formation I crystal of comparative example 1 and crystal formation II crystal of comparative example 2 to the present invention
Carry out such as stability inferior contrast experiment.
Above-mentioned crystal prototype is handled as follows respectively:
It is 92.5%, 25 DEG C at relative humidity to place 1 month；
60 DEG C, place 1 month under intensity of illumination 6000lx；
After period is 1 month, separately sampled XRD and HPLC that carry out analyzes.
XRD analysis result shows: above-mentioned crystal does not all occur crystal formation to change after above-mentioned high temperature, high temperature & photo-irradiation treatment.
Table 4 show HPLC purity detecting result.
Table 4 HPLC purity detecting result
From table 4 result: crystal formation I crystal poor stability under high temperature (60 DEG C) illumination (intensity of illumination 6000lx),
Maximum single miscellaneous content is changed to 0.41% by 0.10%, adds 3.1 times；Although crystal formation II crystal is in high temperature (60 DEG C) illumination
Stability under (intensity of illumination 6000lx) is preferable, and maximum single miscellaneous content is only changed to 0.15% by 0.12%, but crystal formation II
Crystal poor stability under high humidity (relative humidity is 92.5%, 25 DEG C), maximum single miscellaneous content is changed to 0.48% by 0.12%,
Add 3 times；And the safe ground azoles amine phosphate ester crystalline solid stability under high humidity and high temperature illumination of the present invention is the highest,
Big single miscellaneous content is respectively less than 0.1%, illustrates that high humidity, light and heat photograph are stablized by the safe ground azoles amine phosphate ester crystalline solid of the present invention
Property is substantially better than existing crystal formation I crystal and crystal formation II crystal, is very beneficial for the quality control of follow-up preparation.
Dissolubility is tested
Take the safe ground azoles amine phosphate ester knot of crystal formation I crystal of comparative example 1, crystal formation II crystal of comparative example 2 and the present invention respectively
The each 20.0mg of crystal, is separately added into 100mL water and stirs 10 hours at 25 DEG C, and centrifugal filtration takes supernatant and carries out HPLC respectively
Assay, test result is: crystal formation I crystal dissolubility in water is only 0.10mg/mL, and crystal formation II crystal is in water
Dissolubility slightly improve, for 0.16mg/mL, and the safe ground azoles amine phosphate ester crystalline solid dissolubility in water of the present invention shows
Write and improve, for 0.80mg/mL.
The most visible: the safe ground azoles amine phosphate ester crystalline solid that the present invention provides, not only under high humidity, light and heat shine, all has
There is high stability, and the dissolubility in water is significantly improved, be especially suitable for application and the production of pharmaceutical preparation, have
Substantially industrial application value.
Finally be necessary it is pointed out here that: above example is served only for being described further technical scheme, no
Be understood that as limiting the scope of the invention, those skilled in the art make according to the foregoing of the present invention some
Nonessential improvement and adjustment belong to protection scope of the present invention.
Claims (9)
1. a safe ground azoles amine phosphate ester crystalline solid, it is characterised in that: under X-ray powder diffraction, at angle of diffraction 2 θ
Be 11.9 °, 13.8 °, 14.8 °, 15.4 °, 15.6 °, 16.3 °, 17.1 °, 20.7 °, 20.9 °, 22.0 °, 23.8 °, 24.5 °,
Having main characteristic peak at 27.5 °, test error is ± 0.2 °；Described main characteristic peak refers to the peak of relative intensity >=20%.
Safe ground the most according to claim 1 azoles amine phosphate ester crystalline solid, it is characterised in that: under X-ray powder diffraction,
Angle of diffraction 2 θ be 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 °, there is feature at 28.8,33.9
Peak, test error is ± 0.2 °；Described characteristic peak refers to the peak of relative intensity ＞ 5%.
3. the method for the safe ground azoles amine phosphate ester crystalline solid that a kind is prepared described in claim 1 or 2, it is characterised in that include
Following steps:
A) at 30～50 DEG C, safe ground azoles amine phosphate ester and organic solvent and water the mixed solution formed is concentrated into original volume
1/3～2/3；Described organic solvent selected from methanol, ethanol, acetone, acetonitrile, oxolane, N,N-dimethylformamide,
Any one in N-Methyl pyrrolidone, ethyl acetate, thionyl chloride；Organic solvent is 100:1～1 with the volume ratio of water:
1；Safe ground azoles amine phosphate ester content in mixed solution is 0.01～1.0g/mL；
B) being cooled to 0～10 DEG C, the mixed solution and dripping anti-solvent after concentrating through step a) is to there is muddiness, and insulation is stirred
Mix 1～3 hour；Described anti-solvent appointing in methyl tertiary butyl ether(MTBE), diisopropyl ether, normal hexane, Pentamethylene., pentane
A kind of；
C) crystal of precipitation is collected by filtration, is dried at 40～90 DEG C, obtain described safe ground azoles amine phosphate ester crystalline solid.
4. method as claimed in claim 3, it is characterised in that: the mixed solution described in step a) is by safe ground azoles amine phosphoric acid
Ester raw material is directly dissolved in by mixing that described organic solvent and water are formed for 100:1～1:1 by volume at 10～100 DEG C
Bonding solvent obtains.
5. method as claimed in claim 3, it is characterised in that: the mixed solution described in step a) is by safe ground azoles amine phosphoric acid
Ester disodium salt is first dissolved in by mixing that water and described organic solvent are formed for 50:1～1:1 by volume at 10～100 DEG C
In bonding solvent, add again after being acidified identical organic solvent to the volume ratio of the organic solvent in system with water be 100:1～
1:1 obtains.
6. the method for the safe ground azoles amine phosphate ester crystalline solid that a kind is prepared described in claim 1 or 2, it is characterised in that include
Following steps:
A) at 30～100 DEG C, safe ground azoles amine phosphate ester raw material is made to be dissolved completely in solvent；Described solvent be organic solvent or
Organic solvent and water are the mixed solvent that 100:1～1:10 is formed by volume；Described organic solvent is organic amine solvent
Or amide solvent, include but not limited to DMF, N,N-dimethylacetamide, pyridine；
B) the solution Temperature fall to 40～60 DEG C that step A obtains, insulated and stirred 1～3 hours are made；The most certainly
So cool to 0～10 DEG C；
C) crystal of precipitation is collected by filtration, is dried at 40～90 DEG C, obtain described safe ground azoles amine phosphate ester crystalline solid.
7. the method for the safe ground azoles amine phosphate ester crystalline solid that a kind is prepared described in claim 1 or 2, it is characterised in that include
Following steps:
1. at 20～40 DEG C, making safe ground azoles amine organic phosphate disodium salt be dissolved completely in organic solvent with water is 100 by volume:
In the 1～1:100 mixed solvent formed；Described organic solvent is organic amine solvent or amide solvent, includes but not limited to
N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, pyridine；
2. the solution 1. obtained step is acidified, and the pH making solution is 0.5～4；
3. add the organic solvent the most identical with step, make the volume ratio of organic solvent in solution system and water be 100:1～
1:100, is then heated to 60～80 DEG C, obtains settled solution；
4. the solution Temperature fall to 40～60 DEG C that 3. step obtains, insulated and stirred 1～3 hours are made；The most certainly
So cool to 0～10 DEG C；
5. the crystal of precipitation is collected by filtration, is dried at 40～90 DEG C, obtain described safe ground azoles amine phosphate ester crystalline solid.
8. the method as described in claim 4 or 6, it is characterised in that: described safe ground azoles amine phosphate ester raw material is known
Meaning kenel.
9. the method as described in claim 5 or 7, it is characterised in that: described safe ground azoles amine organic phosphate disodium salt is known
Arbitrarily kenel.
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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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| CN102439006A (en) * | 2009-02-03 | 2012-05-02 | 特留斯治疗学公司 | Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate |
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