CN108948079A - A kind of specially azoles amine di-ammonium salts and crystal form and preparation method - Google Patents
A kind of specially azoles amine di-ammonium salts and crystal form and preparation method Download PDFInfo
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- CN108948079A CN108948079A CN201710346079.7A CN201710346079A CN108948079A CN 108948079 A CN108948079 A CN 108948079A CN 201710346079 A CN201710346079 A CN 201710346079A CN 108948079 A CN108948079 A CN 108948079A
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- tedizolid phosphate
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- 239000013078 crystal Substances 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- -1 azoles amine Chemical class 0.000 title claims description 14
- 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 claims abstract description 46
- 229960003947 tedizolid phosphate Drugs 0.000 claims abstract description 45
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 14
- 229910002483 Cu Ka Inorganic materials 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000908 ammonium hydroxide Substances 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 238000005352 clarification Methods 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- XRURWBKRKZLENR-UHFFFAOYSA-N azane;ethane-1,2-diol Chemical compound N.OCCO XRURWBKRKZLENR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 5
- UKLUVTJTFDQVJG-UHFFFAOYSA-N azane ethane-1,2-diol methanol Chemical compound N.CO.C(CO)O UKLUVTJTFDQVJG-UHFFFAOYSA-N 0.000 claims 1
- 230000005855 radiation Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000003851 azoles Chemical class 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000746 purification 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
- 241000894006 Bacteria Species 0.000 description 1
- LHAPORKCQRRIRG-ZETCQYMHSA-N CC([C@@H]1CN[I]=CC1)=C Chemical compound CC([C@@H]1CN[I]=CC1)=C LHAPORKCQRRIRG-ZETCQYMHSA-N 0.000 description 1
- 0 C[C@]1C(C)(C)[C@]1[C@](*)F Chemical compound C[C@]1C(C)(C)[C@]1[C@](*)F 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 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 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940056137 sivextro Drugs 0.000 description 1
- 230000036548 skin texture Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance 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 present invention provides a kind of Tedizolid Phosphate di-ammonium salts and novel crystal forms and preparation method, compared with the salt disclosed in the existing patent, Tedizolid Phosphate di-ammonium salts are with good stability, preparation process is easier, with the more preferable advantage of refining effect, Tedizolid Phosphate diammonium salt compound, structure are as follows:
Description
Technical field
The present invention relates to a kind of specially azoles amine diammonium salt production process and novel crystal forms, belong to medicinal chemistry arts
Background technique
06 month 2014 a kind of new oxazolidone antibiotics Sivextro (tedizolid phosphate, phosphoric acid spy
Ground azoles amine) U.S. FDA approval is obtained, for treating staphylococcus aureus (including methicillin resistant strains, methicillin-sensitivity
Bacterial strain) and the gram-positive bacteriums such as various streptococcuses and enterococcus faecalis caused by acute bacterial skin and skin texture sense
It contaminates (ABSSSI).Such drug has completely new antibacterial mechanisms, to the Grain-positive of gram-positive cocci, especially multidrug resistant
Coccus has stronger antibacterial activity, and crossing drug resistant phenomenon is not present with other drugs.The medicine be by South Korea Dong-A,
The cooperative development of the companies such as Cubist pharmaceuticals and Bayer, 03 month 2015 granted in Europe.It is same at present with the country
Class medicine Linezolid is compared, and is significantly reduced in intestines and stomach and decrease of platelet adverse reaction, and the incidence liquid of drug resistance is lower.
Tedizolid Phosphate structural formula is as shown in following formula 1:
Since specially azoles amine phosphate dissolubility in most of organic solvent is poor, directly results in purification effect and pay no attention to
Think, but specially its water solubility of azoles amine phosphate is very good, can be dissolved in water or water and organic solvent in the mixed solvent, is a kind of
Very important pharmaceutical salts or preparation specially azoles amine phosphate key intermediate compound.Dong A Pharm. Co., Ltd is for the first time in
State is disclosed complicated about disodium salt method is obtained in specially azoles amine disodic alkaliine patent CN1894242A, and uses sodium methoxide
Equal highly basic, obtained disodium salt impurity are more.Patent CN104530128A has used the complicated highly basic such as trityl sodium, and uses molten
Agent type is more, complicated for operation to make troubles to large-scale production.
Patent CN102439006A report, specifically, most of identified salt are difficult to be prepared into crystal form, or unstable
Calmly, when such as in purifying or dry form.For example, not detecting stable hydrate form about mono-sodium salt.Separately
Outside, containing the water for being by weight more than 10% in the material, therefore hygroscopicity is very strong, so not being suitable for required purposes.
Disodium salt crystal hydrate is formd, but its is unstable, and containing by weight 19.6% water, still, the disodium salt is
It is easily dissolved, hydrate drying is generated into amorphous state sample.The water content of amorphous state sample is by weight about
6.2%.For di-potassium, it is not separated to crystalline solid material.Half calcium salt can be prepared into crystal, however the crystal has and do not conform to
Suitable hygroscopicity.Hemimagnesium salt crystalline material can be formed, and seem a variety of hydrates comprising salt, however, a variety of polymorphs
Presence cause it not to be suitable in preparation.In an experiment, the fusing point of magnesium salts is 152.8 DEG C, is shown in such case
The lower material specific ionization acid is more unstable.
Summary of the invention
The present invention provides a kind of Tedizolid Phosphate di-ammonium salts and novel crystal forms and preparation method, and disclosed in existing patent
Salt compare, Tedizolid Phosphate di-ammonium salts are with good stability, and preparation process is easier to be reliable, have refining effect more
Good advantage.Tedizolid Phosphate di-ammonium salts structural formula is as shown in following formula 2:
The present invention provides the crystal form I of Tedizolid Phosphate di-ammonium salts, and the crystal form I is radiated using Cu-Ka, with 2 θ angles
The X-ray powder diffraction of expression at 10.1 ± 0.2 °, 11.4 ± 0.2 °, 16.7 ± 0.2 °, 17.6 ± 0.2 °, 20.1 ± 0.2 °,
There is characteristic peak at 23.7 ± 0.2 °, 26.7 ± 0.2 °, 29.8 ± 0.2 °, more specifically at 10.1 ± 0.2 °, 11.4 ± 0.2 °, 11.8
± 0.2 °, 12.3 ± 0.2 °, 12.7 ± 0.2 °, 13.4 ± 0.2 °, 13.7 ± 0.2 °, 14.5 ± 0.2 °, 14.7 ± 0.2 °,
14.6±0.2°,15.2±0.2°,15.7±0.2°,16.1±0.2°,16.7± 0.2°,17.6±0.2°,19.2±
0.2°,19.5±0.2°,20.1±0.2°,21.7±0.2°,22.8±0.2°,23.7±0.2°,24.2±0.2°,25.3±
0.2°, 25.9±0.2°,26.7±0.2°,29.8±0.2°,30.3±0.2°,31.1±0.2°,32.8±0.2°,33.7
There is characteristic peak at ± 0.2 °, 35.9 ± 0.2 °.
Crystal form I of the present invention, is radiated using Cu-Ka, and the X-ray powder diffraction (XRPD) indicated with 2 θ angles has
Map as shown in Figure 1.
The present invention provides the crystal form II of Tedizolid Phosphate di-ammonium salts, and the crystal form II is radiated using Cu-Ka, with 2 angles θ
Spend the X-ray powder diffraction indicated at 13.7 ± 0.2 °, 14.4 ± 0.2 °, 14.8 ± 0.2 °, 15.2 ± 0.2 °, 17.4 ±
There is characteristic peak at 0.2 °, 18.9 ± 0.2 °, 20.1 ± 0.2 °, 22.1 ± 0.2 °, 24.4 ± 0.2 °, 25.6 ± 0.2 °；
Crystal form II of the present invention, is radiated using Cu-Ka, and the X-ray powder diffraction (XRPD) indicated with 2 θ angles has
Map as shown in Figure 2.
The crystal form II of above-mentioned Tedizolid Phosphate di-ammonium salts is detected through differential scanning calorimeter (DSC-TGA) it is found that its DSC
Map has obvious endothermic peak in 178.4~211.4 DEG C of ranges as shown in Figure 4；Specifically, the peak value of DSC map endothermic peak goes out
Present 197.0 DEG C；It synchronizes thermogravimetric analysis (TGA) display, crystal form II weightlessness 3.4% within the scope of 37.8~176.2 DEG C.
The present invention provides the crystal form III of Tedizolid Phosphate di-ammonium salts, and the crystal form III is radiated using Cu-Ka, with 2 θ
The X-ray powder diffraction that angle indicates has characteristic peak at 14.9 ± 0.2 °, 25.3 ± 0.2 °；
Crystal form III of the present invention, is radiated using Cu-Ka, X-ray powder diffraction (XRPD) tool indicated with 2 θ angles
Just like map shown in Fig. 3.
The crystal form III of above-mentioned Tedizolid Phosphate di-ammonium salts through differential scanning calorimeter (DSC-TGA) detect it is found that its
DSC map, as shown in figure 5, having obvious endothermic peak in 178.9~213.0 DEG C of ranges；Specifically, DSC map endothermic peak
Peak value appears in 196.7 DEG C；It synchronizes thermogravimetric analysis (TGA) display, and crystal form III is weightless within the scope of 37.4~165.5 DEG C
0.19%.
It is provided by the present invention it is a kind of prepare Tedizolid Phosphate di-ammonium salts method, reaction route is as follows:
Wherein, alkali is selected from the solution of ammonium hydroxide or ammonia.
The wherein further preferred ammonium hydroxide of alkali, ammonia ether, ammonia methanol, ammonia ethyl alcohol, ammonia ethylene glycol, ammonia methanol second
Glycol mixed solvent, ammonia ethyl alcohol ethylene glycol mixed solvent, further preferably ammonium hydroxide, more preferable 25-28% ammonium hydroxide.
The present invention provides a kind of preparation method of Tedizolid Phosphate di-ammonium salts crystal form, the steps include: specially azoles amine crude product
It is added in water, ammonium hydroxide reaction is added, adjusts pH value, is filtered after stirring dissolved clarification, organic solvent, stirring and crystallizing is added dropwise into filtrate.
(1) it is dried with nitrogen after separating or room temperature in vacuo is dry, obtain Tedizolid Phosphate di-ammonium salts crystal form I；
(2) 35-45 DEG C of vacuum drying, obtains Tedizolid Phosphate di-ammonium salts crystal form II, drying temperature preferably 40 after separating
℃；
(3) 55-65 DEG C of vacuum drying, obtains Tedizolid Phosphate di-ammonium salts crystal form III, drying temperature preferably 60 after separating
℃。
It is wherein above-mentioned a kind of to prepare Tedizolid Phosphate di-ammonium salts method and prepare the organic solvent that crystal form method uses with this
Be selected from one of acetone, acetonitrile, methanol, ethyl alcohol, isopropanol, tetrahydrofuran or any combination thereof, preferably acetone, acetonitrile,
One of tetrahydrofuran or any combination thereof, most preferably acetone.Specially azoles amine crude product quality g and water volume ml/, organic solvent
Volume ml/ is also than for 1:(9~11): (25~35)；It is preferred that 1:10:30.
Wherein pH value is preferably 8-12, further preferred 9-10.
Wherein reaction temperature and stirring and crystallizing temperature are 5-35 DEG C, and preferably 15-25 DEG C；The stirring and crystallizing time be 0.5~
3h, preferably 1~1.5h.
It is used to prepare the present invention also provides a kind of new Tedizolid Phosphate di-ammonium salts or its crystal form or purifying phosphoric acid is special
Ground azoles drug amine.
Tedizolid Phosphate di-ammonium salts and its crystal form provided by the invention have fine stability, are no crystal water chemical combination
Object can save for a long time at room temperature.The salt and its crystal form preparation process are easier, reliable, relative to phosphoric acid specially azoles
Amine has good solubility, is suitble to medicinal, and is convenient for purification, is a kind of important intermediate compound of Tedizolid Phosphate
Object.
Detailed description of the invention
The X-RPD map of Fig. 1 Tedizolid Phosphate di-ammonium salts crystal form I；
The X-RPD map of Fig. 2 Tedizolid Phosphate di-ammonium salts crystal form II；
The X-RPD map of Fig. 3 Tedizolid Phosphate di-ammonium salts crystal form III；
Differential scanning calorimetry (DSC-TGA) map of Fig. 4 Tedizolid Phosphate di-ammonium salts crystal form II；
Differential scanning calorimetry (DSC-TGA) map of Fig. 5 Tedizolid Phosphate di-ammonium salts crystal form III；
The HPLC map of Fig. 6 Tedizolid Phosphate di-ammonium salts crystal form I；
The HPLC map of Fig. 7 Tedizolid Phosphate di-ammonium salts crystal form II；
The HPLC map of Fig. 8 Tedizolid Phosphate di-ammonium salts crystal form III.
Specific embodiment:
Below by specific embodiment, the present invention is described further, but the protection model being not intended to restrict the invention
It encloses.Hereinafter if not specified, the operation that the present invention is carried out is the progress under room temperature of this neighborhood routine.
1 Tedizolid Phosphate di-ammonium salts crystal form I of embodiment preparation:
Tedizolid Phosphate crude product 80g (HPLC purity 98.8%, largest single impurity 0.6%) is put into reaction flask, is added
800ml water, room temperature condition stirring, is added dropwise 25% ammonium hydroxide, adjusts pH=9-10, filters after solid dissolved clarification, be added dropwise into filtrate
2400ml acetone, precipitates crystal, and stirs 1h, filters, filter cake 160ml Acetone rinse, and the dry 16h of room temperature in vacuo obtains phosphoric acid
Specially azoles amine di-ammonium salts crystal form I, yield 87.0%, purity 99.76%.
After measured, X-RPD map is as shown in Figure 1, HPLC map is as shown in Figure 6
2 Tedizolid Phosphate di-ammonium salts crystal form II of embodiment preparation:
Tedizolid Phosphate crude product 80g (HPLC purity 98.8%, largest single impurity 0.6%) is put into reaction flask, is added
800ml water, room temperature condition stirring, is added dropwise 25% ammonium hydroxide, adjusts PH=9-10, filters after solid dissolved clarification, be added dropwise into filtrate
2400ml methanol, precipitates crystal, and stirs 1h, filters, and filter cake 160ml Acetone rinse, 40 DEG C of vacuum drying 16h obtain phosphoric acid
Specially azoles amine di-ammonium salts crystal form II, yield 76.2%, purity 99.77%.
After measured, X-RPD map as shown in Fig. 2, its DSC-TGA map as shown in figure 4, HPLC map as shown in Fig. 6
3 Tedizolid Phosphate di-ammonium salts crystal form III of embodiment preparation:
Tedizolid Phosphate crude product 80g (HPLC purity 98.8%, largest single impurity 0.6%) is put into reaction flask, is added
800ml water, room temperature condition stirring, is added dropwise 25% ammonium hydroxide, adjusts PH=9-10, filters after solid dissolved clarification, be added dropwise into filtrate
2400ml acetone, precipitates crystal, and stirs 1h, filters, and filter cake 160ml Acetone rinse, 60 DEG C of vacuum drying 16h obtain phosphoric acid
Specially azoles amine di-ammonium salts crystal form III, yield 85.6%, purity 99.74%.
After measured, X-RPD map as shown in figure 3, its DSC-TGA map as shown in figure 5, HPLC map such as Fig. 7 institute
Show, purity:
Claims (12)
1. a kind of Tedizolid Phosphate diammonium salt compound, structure are as follows:
2. compound according to claim 1, which is characterized in that the crystal form of the Tedizolid Phosphate di-ammonium salts selects
From one of crystal form I, crystal form II, crystal form III, a variety of or its mixed crystal；The crystal form I, is radiated using Cu-Ka, with 2 θ angles
The X-ray powder diffraction of expression at 10.1 ± 0.2 °, 11.4 ± 0.2 °, 16.7 ± 0.2 °, 17.6 ± 0.2 °, 20.1 ± 0.2 °,
There is characteristic peak at 23.7 ± 0.2 °, 26.7 ± 0.2 °, 29.8 ± 0.2 °；The crystal form II, is radiated using Cu-Ka, with 2 θ angles
The X-ray powder diffraction of expression at 13.7 ± 0.2 °, 14.4 ± 0.2 °, 14.8 ± 0.2 °, 15.2 ± 0.2 °, 17.4 ± 0.2 °,
There is characteristic peak at 18.9 ± 0.2 °, 20.1 ± 0.2 °, 22.1 ± 0.2 °, 24.4 ± 0.2 °, 25.6 ± 0.2 °；The crystal form III,
It is radiated using Cu-Ka, has characteristic peak at 14.9 ± 0.2 °, 25.3 ± 0.2 ° with the X-ray powder diffraction that 2 θ angles indicate.
3. compound according to claim 2, which is characterized in that the crystal form I, Cu- of the Tedizolid Phosphate di-ammonium salts
Ka radiation, the X-ray powder diffraction indicated with 2 θ angles at 10.1 ± 0.2 °, 11.4 ± 0.2 °, 11.8 ± 0.2 °, 12.3 ±
0.2 °, 12.7 ± 0.2 °, 13.4 ± 0.2 °, 13.7 ± 0.2 °, 14.5 ± 0.2 °, 14.7 ± 0.2 °, 14.6 ± 0.2 °, 15.2 ±
0.2°,15.7±0.2°,16.1±0.2°,16.7±0.2°,17.6±0.2°,19.2±0.2°,19.5±0.2°,20.1±
0.2°,21.7±0.2°,22.8±0.2°,23.7±0.2°,24.2±0.2°,25.3±0.2°,25.9±0.2°,26.7±
There is spy at 0.2 °, 29.8 ± 0.2 °, 30.3 ± 0.2 °, 31.1 ± 0.2 °, 32.8 ± 0.2 °, 33.7 ± 0.2 °, 35.9 ± 0.2 °
Levy peak.
4. compound according to claim 2, which is characterized in that the crystal form II of the Tedizolid Phosphate di-ammonium salts exists
178.4~211.4 DEG C of ranges have obvious endothermic peak, and crystal form III has obvious endothermic peak in 178.9~213.0 DEG C of ranges.
5. a kind of preparation method of compound as described in claim 1, which is characterized in that reaction route is as follows:
Wherein, alkali is selected from the solution of ammonium hydroxide or ammonia.
6. preparation method according to claim 5, which is characterized in that the alkali is selected from ammonium hydroxide, ammonia ether, ammonia first
Alcohol, ammonia ethyl alcohol, ammonia ethylene glycol, ammonia methanol ethylene glycol mixed solvent, ammonia ethyl alcohol ethylene glycol mixed solvent, preferably ammonia
Water, more preferable 25-28% ammonium hydroxide.
7. a kind of preparation method of compound according to claim 2, method includes the following steps:
Specially azoles amine crude product is added in water, ammonium hydroxide reaction is added, adjusts pH value, filters after stirring dissolved clarification, is added dropwise into filtrate
Organic solvent, stirring and crystallizing are dry by the following method later that crystal form I, II and III are made respectively:
(1) room temperature is dried with nitrogen after separating or room temperature in vacuo is dry, obtains Tedizolid Phosphate di-ammonium salts crystal form I；
(2) 35-45 DEG C of vacuum drying, obtains Tedizolid Phosphate di-ammonium salts crystal form II after separating, and preferably 40 DEG C of drying temperature；
(3) 55-65 DEG C of vacuum drying, obtains Tedizolid Phosphate di-ammonium salts crystal form III after separating, and preferably 60 DEG C of drying temperature.
8. the preparation method according to one of claim 5-7, which is characterized in that the organic solvent be selected from acetone, acetonitrile,
One of one of methanol, ethyl alcohol, isopropanol, tetrahydrofuran or any combination thereof, preferably acetone, acetonitrile, tetrahydrofuran
Or any combination thereof, most preferably acetone.
9. the preparation method according to one of claim 5-7, which is characterized in that the specially azoles amine crude product quality g and water
Volume ml/, organic solvent volume ml/ ratio are 1:(9~11): (25~35)；It is preferred that 1:10:30.
10. preparation method according to claim 7, which is characterized in that the pH value is 8-12, preferably 9-10.
11. preparation method according to claim 7, which is characterized in that reaction temperature and stirring and crystallizing temperature are 5-35
DEG C, preferably 15-25 DEG C；The stirring and crystallizing time is 0.5~3h, preferably 1~1.5h.
12. a kind of be used to prepare Tedizolid Phosphate drug using compound described in claim 1-4.
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