CN106046088B - Crystal form H3 of rope fluorine cloth Wei and preparation method thereof - Google Patents

Crystal form H3 of rope fluorine cloth Wei and preparation method thereof Download PDF

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CN106046088B
CN106046088B CN201610515840.0A CN201610515840A CN106046088B CN 106046088 B CN106046088 B CN 106046088B CN 201610515840 A CN201610515840 A CN 201610515840A CN 106046088 B CN106046088 B CN 106046088B
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crystal
fluorine cloth
cloth wei
rope fluorine
deliquescence
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CN106046088A (en
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胡咏波
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CHARM PHARMATECH (NANJING) Co Ltd
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CHARM PHARMATECH (NANJING) Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06Pyrimidine radicals
    • C07H19/10Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

The present invention is the divisional application of patent " crystal form of rope fluorine cloth Wei and preparation method thereof ".Crystal form crystal form H3 and the method that is used to prepare this crystal form the invention discloses rope fluorine cloth Wei.The structure and cell parameter of this rope fluorine cloth Wei novel crystal forms are determined using monocrystalline X x ray diffraction analysis xs.2 θ of the crystal form H3 angles of diffraction has characteristic peak in 5.1 °, 6.7 °, 7.1 °, 9.6 °, 15.8 °, 17.2 °, 19.3 °, 19.9 °, 20.7 °, 24.9 ° etc..The crystal form of this new rope fluorine cloth Wei has the advantages that physicochemical property is excellent, stability is good, dissolubility is good, preparation manipulation is simple respectively.

Description

Crystal form H3 of rope fluorine cloth Wei and preparation method thereof
The present patent application is November 7 2014 applying date, application number 201410624111.X, denomination of invention " rope fluorine cloth The divisional application of crystal form of Wei and preparation method thereof ".
Technical field
The present invention relates to rope fluorine cloth Wei (isopropyl (2S) -2- [[[(2R, 3R, 4R, 5R) -5- (2,4-dioxypyrimidine -1- Base) the fluoro- 3- hydroxy-4-methyls of -4--tetrahydrofuran -2- bases]-Difluoro-phenoxy-phosphoryl] amino] propionic ester, chemistry Formula:C22H29FN3O9P four kinds of novel crystalline forms) and preparation method thereof.
Background technology
Rope fluorine cloth Wei (sofosbuvir), entitled isopropyl (2S) -2- [[[(2R, 3R, 4R, the 5R) -5- (2,4- bis- of chemistry Oxygen pyrimidine -1- bases) the fluoro- 3- hydroxy-4-methyls of -4--tetrahydrofuran -2- bases]-Difluoro-phenoxy-phosphoryl] amino] propionic acid Ester, CAS numberings are 1190307-88-0, and chemical structural formula is as follows:
Rope fluorine cloth Wei is a kind of NS5B polymerase inhibitors developed by Ji Leadd B.V of the U.S. (Glead Sciences), It can block a kind of required specific proteins of hepatitis c viral replication individually or when being used in combination with other medicines Matter, for the treatment of hepatitis C.On rope fluorine cloth Wei is ratified in December, 2013 by U.S. Food and Drug Administration City, trade name Sovaldi.Rope fluorine cloth Wei is the first granted medicine available for the full oral medication of hepatitis C, for spy When determining the treatment of genotype chronic hepatitis C, the demand to conventional injection interfering effects of drug plain (IFN) can be eliminated, it is contemplated that 2014 complete Ball sales volume has a vast market prospect more than 10,000,000,000 dollars.
United States Patent (USP) US20110251152 describes 6 kinds of crystal forms of rope fluorine cloth Wei and teaches wherein crystal form form's 6 Preparation method.6 kinds of crystal forms described in this document are as follows:
Crystal form Form 1, its powder x-ray diffraction characteristic peak are 5.2 °, 7.5 °, 9.6 °, 16.7 °, 18.3 °, 22.2 °.Specially Sharp US20110251152 does not instruct the specific preparation method of crystal form form 1, it is indicated that crystal form form 1 can be by crystal form Form2~5 are transformed.The hygroscopicity of crystal form form 1 itself is stronger, is easily transformed into spawn in open-top receptacle or turns Turn to crystal form form 6.
Crystal form form 2 be dichloromethane solvate crystallization, its powder x-ray diffraction characteristic peak for 4.9 °, 6.9 °, 9.8°、19.8°、20.6°、24.7°、26.1.Crystal form form 2 is crystallized from dichloromethane and obtained, and crystal form is converted into when dry form 1。
Crystal form form 3 is chloroform crystalline solvate, its powder x-ray diffraction characteristic peak is 6.9 °, 9.8 °, 19.7°、20.6°、24.6°.Crystal form form 3 is crystallized from chloroform and obtained, and crystal form form 1 is converted into when dry.
Crystal form form 4, its powder x-ray diffraction characteristic peak are 5.0 °, 6.8 °, 19.9 °, 20.6 °, 24.6 °.Crystal form Form 4 is crystallized from acetonitrile and obtained, and property is unstable, and crystal form form 1 is converted into when being separated by filtration.
Crystal form form 5, its powder x-ray diffraction characteristic peak are 5.2 °, 6.6 °, 7.1 °, 15.7 °, 19.1 °, 25.0 °.It is brilliant Type form 5 is crystallized from methyl phenyl ethers anisole and obtained, and property is unstable, and crystal form form 1 is converted into when being separated by filtration.
Crystal form form 6, its powder x-ray diffraction characteristic peak for 6.1 °, 8.2 °, 10.4 °, 12.7 °, 17.2 °, 17.7 °, 18.0°、18.8°、19.4°、19.8°、20.1°、20.8°.Patent US20110251152, which is disclosed, following two prepares crystal form The method of form 6, is obtained from the conversions of crystal form form 1:
1) gelling material was formed by several days under 1 powder of crystal form form humidity disposed within, by gelling material grind into powder (its powder x-ray diffraction is identical with form 1).This powder is placed in open containers sample after 6-10 weeks and slowly becomes brilliant Type form 6.
2) it will add in the water of 5~50 mg/mls, stirred at room temperature or 50 DEG C, crystal form under 1 room temperature of crystal form form Form 1 is converted into crystal form form 6 within a few hours.
There are stability is relatively low, solubility is relatively low, production technology to some extent for the crystal form of existing six kinds of ropes fluorine cloth Wei The shortcomings of repeatability is poor, this directly affects production, storage and its pharmaceutical preparation of rope fluorine cloth Wei bulk pharmaceutical chemicals in the third type liver Effect in inflammation treatment.
It is well known that the crystal habit of medicine can largely influence the characteristic of medicine, such as chemical stability, Fusing point, solubility, rate of dissolution etc..And these characteristics can directly affect the production, storage and use of bulk pharmaceutical chemicals and preparation. Therefore, the crystalline form of control cord fluorine cloth Wei is most important for obtaining outstanding rope fluorine cloth Wei pharmaceutical preparation, it is intended that exploitation Go out the new novel crystalline form with higher stability, higher solubility and the rope fluorine cloth Wei for being easier to preparation.
The content of the invention
It is an object of the invention to provide the new rope fluorine cloth Wei crystal form with more excellent physicochemical property, and it is used to prepare The method of these crystal forms.
The inventors of the present invention are concentrated on studies for solve the problem, as a result have surprisingly been discovered that four kinds newly Rope fluorine cloth Wei crystal form H1, crystal form H2, crystal form H3 and crystal form H4.Wherein, crystal form H1 is the hydrate knot containing 1: 1 hydrone Crystalline substance, crystal form H2 are the methanol solvate crystallization containing 1: 1 methanol molecules, and crystal form H3 is the ethanolates crystallization containing 1: 1 ethanol molecule, brilliant Type H4 is the hexichol etherate crystallization containing 1: 1 diphenyl ether molecule.In addition, the present inventors have additionally discovered that respectively selectively obtain crystal form H1, crystal form H2, the preparation method of crystal form H3 and crystal form H4.These four novel crystalline form states are excellent, stable with physicochemical property respectively The advantages that property is good, dissolubility is good, preparation manipulation is simple, has superiority in industrial production and medical applications.
The angle of diffraction 2 θs of the crystal form H1 that the present invention announces in using the Alpha-ray x-ray diffractogram of powder spectrums of Cu-K exists 4.9 °, 6.6 °, 7.1 °, 8.2,9.6 °, 16.5 °, 19.0 °, 19.2 °, 19.9 °, 24.9 ° etc. have characteristic peak.
Confirming after single crystal X-ray diffraction experiment and crystal structure calculate, crystal form H1 belongs to monoclinic system, space group P21, Cell parameter:α=90.00 °, β=108.05 (3) °, γ=90.00 °;Unit cell volumeStructure cell includes asymmetry unit number Z=2, the change in an asymmetry unit Metering-type is C22H31FN3O10P, molecular weight 547.47, crystalline density d=1.251g/cm3.Single crystal X-ray diffraction structure point Analysis confirms to contain 1: 1 hydrone in crystal form H1 lattices.
The crystal form H1 of the present invention has 65~80 in DSC schemes (means of differential scanning calorimetry figure) in the range of 50-200 DEG C Endothermic peak larger at less endothermic peak and 95~110 DEG C at DEG C (its peak temperature is 100.6 DEG C).
The present invention provides the preparation method of crystal form H1, wherein, rope fluorine cloth Wei and water are added to methyl phenyl ethers anisole and butyl oxide The in the mixed solvent of mixed solvent or methyl phenyl ethers anisole and isopropyl ether, is heated to 70~95 DEG C, is then cooled to 0~35 DEG C, is analysed Crystalline substance, crystallization time are 1~10 day, are derived from the crystal form H1 of colourless needles.
In being used to prepare in the method for crystal form H1 for the present invention, methyl phenyl ethers anisole is 3 with the volume ratio of butyl oxide or isopropyl ether: 1~1: 1, it is preferably 1: 1;The ratio of rope fluorine cloth Wei weight (g) and mixed solvent volume (mL) is 1: 5~1: 20, more preferably 1 ∶10;Water is 1: 100~1 with rope fluorine cloth Wei part by weight:20, more preferably 3: 100;Heating-up temperature is preferably 80~85 DEG C;It is excellent Choosing is cooled to 20~25 DEG C;The crystallization time is preferably 3 days.
The angle of diffraction 2 θs of the crystal form H2 of the present invention in using Cu-K Alpha-ray x-ray diffractogram of powder spectrum 6.7 °, 7.0 °, 9.7 °, 19.1 °, 19.3 °, 19.8 °, 20.3 °, 24.9 °, 25.1 °, 25.6 ° etc. have characteristic peak.
Confirm after single crystal X-ray diffraction experiment and crystal structure calculate, crystal form H2 belongs to monoclinic system, and space group P21 is brilliant Born of the same parents' parameter:α=90.00 °, β=108.86 (3) °, γ= 90.00°;Unit cell volumeStructure cell includes asymmetry unit number Z=2, the chemistry meter in an asymmetry unit Amount formula is C23H33FN3O10P, molecular weight 561.49, crystalline density d=1.313g/cm3.Single crystal X-ray diffraction structural analysis is true Recognize in crystal form H2 lattices and contain 1: 1 methanol solvate molecule.
The crystal form H2 of the present invention has a suction at 84~100 DEG C in DSC figures in the range of 50~200 DEG C Thermal spike, peak temperature are 89.1 DEG C.
The present invention provides the preparation method of crystal form H2, wherein, phenylene dimethyl ether solvent between rope fluorine cloth Wei and methanol are added, The mixed solvent of phenylene dimethyl ether and butyl oxide, or the in the mixed solvent of a phenylene dimethyl ether and isopropyl ether, are heated to 70~95 DEG C, so After be cooled to 0~35 DEG C, carry out crystallization, the crystallization time is 1~10 day, is derived from the crystal form H2 of colourless needles.
In being used to prepare in the method for crystal form H2 for the present invention, a phenylene dimethyl ether and butyl oxide or the volume ratio of isopropyl ether For 3: 1~1: 1, more preferably 1: 1;The ratio of rope fluorine cloth Wei weight (g) and solvent volume (mL) is 1: 5~1: 20, is preferably 1 ∶8;Methanol is 1: 20~3: 20 with rope fluorine cloth Wei part by weight, more preferably 1: 10;Heating-up temperature is preferably 80~85 DEG C;It is excellent Choosing is cooled to 20~25 DEG C;The crystallization time is preferably 3 days.
The angle of diffraction 2 θs of the crystal form H3 of the present invention in using Cu-K Alpha-ray x-ray diffractogram of powder spectrum 5.1 °, 6.7 °, 7.1 °, 9.6 °, 15.8 °, 17.2 °, 19.3 °, 19.9 °, 20.7 °, 24.9 ° etc. have characteristic peak.
Confirm after single crystal X-ray diffraction experiment and crystal structure calculate, crystal form H3 belongs to monoclinic system, and space group P21 is brilliant Born of the same parents' parameter:α=90.00 °, β=108.78 (3) °, γ =90.00 °;Unit cell volumeStructure cell includes asymmetry unit number Z=2, the change in an asymmetry unit Metering-type is C24H35FN3O10P, molecular weight 575.52, crystalline density d=1.342g/cm3.Single crystal X-ray diffraction structure point Analysis confirms to contain 1: 1 alcohol solvent molecule in crystal form H3 lattices
The crystal form H3 of the present invention has the endothermic peak at 70~88 DEG C in DSC figures in the range of 50~200 DEG C, Peak temperature is 74.4 DEG C.The crystal form H3 of the present invention is the rope fluorine cloth Wei ethanol solvate containing a molecules of ethanol.
The present invention provides the preparation method of crystal form H3, wherein rope fluorine cloth Wei and ethanol are added in dibenzyl ether solvents, heating To 70~95 DEG C, 0~35 DEG C is then cooled to, carries out crystallization, the crystallization time is 1~10 day, is derived from the crystalline substance of colorless plate Type H3.
In being used to prepare in the method for crystal form H3 for the present invention, the ratio of rope fluorine cloth Wei weight (g) and solvent volume (mL) For 1: 10~1: 20, preferably 1: 10;Ethanol is 1: 50~1: 10 with rope fluorine cloth Wei part by weight, is preferably 1: 20;Heating temperature Degree is preferably 85~90 DEG C;It is preferred that it is cooled to 20~25 DEG C;The crystallization time is preferably 3 days.
The angle of diffraction 2 θs of the crystal form H4 of the present invention in using Cu-K Alpha-ray x-ray diffractogram of powder spectrum 5.5 °, 5.6 °, 10.0 °, 10.9 °, 10.9 °, 16.6 °, 19.8 °, 20.0 °, 20.4 °, 25.0 ° etc. have characteristic peak.
Confirm after Single Crystal X-ray experiment and crystal structure calculate, crystal form H4 belongs to monoclinic system, space group P21, structure cell ginseng Number:α=90.00 °, β=116.64 (3) °, γ= 90.00°;Unit cell volumeStructure cell includes asymmetry unit number Z=2, the chemistry in an asymmetry unit Metering-type is C34H39FN3O10P, molecular weight 699.65, crystalline density d=1.313g/cm3.Single crystal X-ray diffraction structural analysis Confirm in crystal form H4 lattices containing 1: 1 diphenyl ether solvent molecule.
The crystal form H4 of the present invention has a heat absorption at 64~76 DEG C in DSC figures in the range of 50~200 DEG C Peak, peak temperature are 68.1 DEG C.
The present invention provides the preparation method of crystal form H4, wherein rope fluorine cloth Wei is added in hexichol ether solvents, it is heated to 70~ 95 DEG C, 0~35 DEG C is then cooled to, carries out crystallization, the crystallization time is 1~10 day, is derived from the crystal form H4 of colourless needles.
In being used to prepare in the method for crystal form H4 for the present invention, the ratio of rope fluorine cloth Wei weight (g) and solvent volume (mL) For 1: 3~1: 20, preferably 1: 10;Heating-up temperature is preferably 85~90 DEG C;It is preferred that it is cooled to 20~25 DEG C;The crystallization time is preferred For 3 days.
Brief description of the drawings
Fig. 1 is the X-ray monocrystalline molecular structure ellipsoid figure according to the rope fluorine cloth Wei crystal form H1 of the embodiment of the present invention 1;
Fig. 2 is the X-ray powder diffraction figure according to the rope fluorine cloth Wei crystal form H1 of the embodiment of the present invention 1;
Fig. 3 is to be schemed according to the DSC-TGA of the rope fluorine cloth Wei crystal form H1 of the embodiment of the present invention 1;
Fig. 4 is the X-ray monocrystalline molecular structure ellipsoid figure according to the rope fluorine cloth Wei crystal form H2 of the embodiment of the present invention 2;
Fig. 5 is the X-ray powder diffraction figure according to the rope fluorine cloth Wei crystal form H2 of the embodiment of the present invention 2;
Fig. 6 is to be schemed according to the DSC-TGA of the rope fluorine cloth Wei crystal form H2 of the embodiment of the present invention 2;
Fig. 7 is the X-ray monocrystalline molecular structure ellipsoid figure according to the rope fluorine cloth Wei crystal form H3 of the embodiment of the present invention 3;
Fig. 8 is the X-ray powder diffraction figure according to the rope fluorine cloth Wei crystal form H3 of the embodiment of the present invention 3;
Fig. 9 is to be schemed according to the DSC-TGA of the rope fluorine cloth Wei crystal form H3 of the embodiment of the present invention 3;
Figure 10 is the X-ray monocrystalline molecular structure ellipsoid figure according to the rope fluorine cloth Wei crystal form H4 of the embodiment of the present invention 4;
Figure 11 is the X-ray powder diffraction figure according to the rope fluorine cloth Wei crystal form H4 of the embodiment of the present invention 4;
Figure 12 is to be schemed according to the DSC-TGA of the rope fluorine cloth Wei crystal form H4 of the embodiment of the present invention 4.
Embodiment
With reference to embodiment, the present invention will be described in more detail, but does not therefore limit the present invention to described Within scope of embodiments.The experimental method of actual conditions is not specified in the following example, carries out according to conventional methods and conditions.
Heretofore described room temperature refers to 10 DEG C~30 DEG C.
In the preparation method for four crystal forms that the present invention announces, rope fluorine cloth Wei Jun uses the method reported by existing literature The rope fluorine cloth Wei (J.Med.Chem.2010,53: 7202-7218) of preparation;Other solvents and reagent using commercially available chemistry it is pure or Analyze net product.
Four kinds of novel crystalline forms that the present invention announces are tested and are characterized with single crystal X-ray diffraction structural analysis.It is single Brilliant X-ray diffraction structural analysis can directly obtain molecular number in the cell parameter, space group, structure cell of crystal, structure cell internal solvent And the stereochemical structure information of molecule, it is most direct, accurate and effective Crystalline form analysis method in current Crystal study means.
Crystal structure determination instrument used in the embodiment of the present invention is Enraf Noius&Enraf Noius companies CAD4/PC single crystal X-ray diffraction instrument, test temperature are 293 (2) K.With graphite monochromatised MoK alpha raysMake Structure elucidation and amendment are carried out with SHELXS-97 (Sheldrick, 1990) and SHELXL-97 (Sheldrick, 1997).Use Program ORTEP obtains monocrystalline molecular structure ellipsoid figure (Fig. 1, Fig. 4, Fig. 7, Figure 10).
Cell parameter has following meanings obtained by crystal structure determination:
A, b, c are the length of side of unit structure cell;
α, beta, gamma are the crystal face angle of unit structure cell;
V is unit cell volume;
Z is contained asymmetry unit number in structure cell.
X-ray powder diffraction instrument device used in the embodiment of the present invention is penetrated for PANalytical companies X ' pert PRO types X Line powder diffractometer.Using Cu-K alpha rays, measured power is 40kV × 250mA, and sweep speed is 5 °/minute, scanning range 4 θ -2 θ of~80 ° (2 θ) are continuously scanned.
The embodiment of the present invention is obtained in X-ray powder diffraction figure (Fig. 2, Fig. 5, Fig. 8, Figure 11), and transverse axis is 2 θ of diffraction maximum Position (unit:Degree);The longitudinal axis is diffraction peak intensity.
Differential scanning amount hot-hot weight (DSC-TGA) analysis determining instrument is Mettler used in the embodiment of the present invention The 1 type synchronous solvings of TGA/DSC of Toledo companies.Measurement range is 25~350 DEG C, and programming rate is 10 DEG C/min, Protected using nitrogen.
The embodiment of the present invention is obtained in differential scanning amount hot-hot weight (DSC-TGA) figure (Fig. 3, Fig. 6, Fig. 9, Figure 12), heat Weight (TGA) figure and calorimetric (DSC) figure are to represent side by side up and down.Transverse axis is temperature (DEG C) wherein in thermal multigraph, and the longitudinal axis is quality (milli Gram), transverse axis is temperature (unit in calorimetric figure:DEG C), the longitudinal axis is power (unit:Milliwatt).
Embodiment 1:The preparation of crystal form H1 monocrystalline.
0.5 gram of rope fluorine cloth Wei and 15 milligrams of water are added to the mixed solvent of 2.5 milliliters of methyl phenyl ethers anisoles and 2.5 milliliters of butyl oxides, This mixture is heated to 80~85 DEG C and stirring is completely dissolved solid, is then slowly cooled to 1~3 DEG C/min of speed Room temperature and at room temperature stand 72 it is small when, pass through filter take out separate out colourless needles crystal form H1 monocrystalline.
Alternatively, phenylene dimethyl ether and 2.5 milliliters between the mixed solvent in above-mentioned preparation method being replaced with 2.5 milliliters Isopropyl ether mixed solvent.
The measure of the x-ray structure of crystal form H1 monocrystalline in embodiment 1.
It is mono- to choose the rope fluorine cloth Wei crystal form H1 that size is 0.30mm × 0.20mm × 0.10mm in the crystal that embodiment 1 obtains Crystalline substance, is placed on single crystal X-ray diffraction instrument, 5532 diffraction datas is collected in the range of 1.20 °≤2 θ≤25.42 °, wherein independently Point diffraction 5310.The data being collected into are through the Lp factors and empirical absorption correction.Using direct method, and through more wheel difference Fouriers Synthesis, finds out whole hydrogen atoms.All non-hydrogen atom coordinates and its equivalent anisotropy displacement parameter are all minimum with complete matrix Square law carries out refine.
Confirm after single crystal X-ray diffraction experiment and crystal structure calculate, rope fluorine cloth Wei crystal form H1 belongs to monoclinic system, empty Between group P21, cell parameter:α=90.00 °, β=108.05 (3) °, γ=90.00 °;Z=2, the stoichiometric equation in an asymmetry unit is C22H31FN3O10P, Molecular weight is 547.47, crystalline density d=1.251g/cm3.Measure obtains the monocrystalline molecular structure ellipsoid of rope fluorine cloth Wei crystal form H1 Figure is as shown in Figure 1, its non-hydrogen atom coordinate data is as shown in table 1.
The non-hydrogen atom coordinate parameters of 1 crystal form H1 of table
The powder x-ray diffraction analysis of the crystal form H1 monocrystalline of embodiment 1:
The crystal form H1 monocrystalline grind into powder that embodiment 1 is obtained, carries out powder x-ray diffraction analysis, its result to it As shown in Figure 2.The X ray diffracting data of crystal form H1 is as shown in table 2 corresponding to Fig. 2.
The powder x-ray diffraction analysis of 2 crystal form H1 of table
According to X-ray diffraction result, the position of 2 θ of characteristic diffraction peak of crystal form H1 is 4.9 °, 6.6 °, 7.1 °, 8.2 °, 9.6 °, 16.5 °, 19.0 °, 19.2 °, 19.9 °, 24.9 ° etc..
Means of differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, the results are shown in Figure 3 for it.
As can be seen from FIG. 3, crystal form H1 has smaller at 65~80 DEG C in thermogravimetric spectrogram in the range of 50~200 DEG C Endothermic peak and 95~110 DEG C at larger endothermic peak.Its differential thermal spectrogram is shown in room temperature to weight-loss ratio in the range of 150 DEG C 2.3%, error range is interior to match with the structure that single-crystal X-ray diffraction analysis obtains.
Embodiment 2:The preparation of crystal form H2 monocrystalline.
Phenylene dimethyl ether solvent between 0.5 gram of rope fluorine cloth Wei and 0.05 gram of methanol are added 5.0 milliliters, being heated to 85~90 DEG C makes Solid is completely dissolved, be then slowly cooled to room temperature with 1~3 DEG C/min of speed and stand at room temperature 24~72 it is small when, lead to The crystal form H2 of colourless needles is taken out in filtering.
Alternatively, phenylene dimethyl ether solvent between 5.0 milliliters in above-mentioned preparation method can be replaced with to 5.0 milliliters of isophthalic two The mixed solvent of methyl ether and 5.0 milliliters of isopropyl ether.
The measure of crystal form H2 crystal structures in embodiment 2.
It is mono- to choose the rope fluorine cloth Wei crystal form H2 that size is 0.20mm × 0.10mm × 0.10mm in the crystal that embodiment 2 obtains Crystalline substance, is placed on single crystal X-ray diffraction instrument, 5446 diffraction datas is collected in the range of 1.21 °≤2 θ≤25.40 °, wherein independently Point diffraction 5216.The data being collected into are through the Lp factors and empirical absorption correction.Using direct method, and through more wheel difference Fouriers Synthesis, finds out whole hydrogen atoms.All non-hydrogen atom coordinates and its equivalent anisotropy displacement parameter are all minimum with complete matrix Square law carries out refine.
Confirm after single crystal X-ray diffraction experiment and crystal structure calculate, rope fluorine cloth Wei crystal form H2 belongs to monoclinic system, space Group P21, cell parameter:α=90.00 °, β=108.86 (3) °, γ=90.00 °; Z=2, the stoichiometric equation in an asymmetry unit is C23H33FN3O10P, Molecular weight is 561.49, crystalline density d=1.313g/cm3
Measure obtains the monocrystalline molecular structure ellipsoid figure of rope fluorine cloth Wei crystal form H2 as shown in figure 4, its non-hydrogen atom coordinate number According to as shown in table 3.
The non-hydrogen atom coordinate parameters of 3 crystal form H2 of table
The powder x-ray diffraction analysis of the crystal form H2 monocrystalline of embodiment 2:
The crystal form H2 monocrystalline grind into powder that embodiment 2 is obtained, carries out powder x-ray diffraction analysis, its result to it As shown in Figure 5.The X ray diffracting data of crystal form H2 is as shown in table 4.
The X-ray diffraction analysis of 4 crystal form H2 powder of table
According to X-ray diffraction result, the position of 2 θ of characteristic diffraction peak of crystal form H2 is 6.7 °, 7.0 °, 9.7 °, 19.1 °, 19.3 °, 19.8 °, 20.3 °, 24.9 °, 25.1 °, 25.6 ° etc..
Means of differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, the results are shown in Figure 6 for it.
As can be seen from FIG. 6, crystal form H2 has an endothermic peak in 84-100 in thermogravimetric spectrogram in the range of 50-200 DEG C ℃.It is 5.5% that its differential thermal spectrogram, which is shown in room temperature to weight-loss ratio in the range of 180 DEG C, is divided in error range with single crystal X-ray diffraction Obtained structure is analysed to match.Embodiment 3:The preparation of crystal form H3 monocrystalline
0.5 gram of rope fluorine cloth Wei is mixed with 25 milligrams of ethanol and 5 milliliters of benzyl ether, heats this mixture to 85~90 DEG C simultaneously Stirring is completely dissolved solid, is then slowly cooled to room temperature with 1~3 DEG C/min of speed and when standing 72 is small at room temperature, The crystal form H3 monocrystalline of the colourless needles separated out is taken out by filtering.
The measure of the crystal form H3 crystal structures of embodiment 3
It is mono- to choose the rope fluorine cloth Wei crystal form H3 that size is 0.30mm × 0.20mm × 0.10mm in the crystal that embodiment 3 obtains Crystalline substance, is placed on single crystal X-ray diffraction instrument, 5460 diffraction datas is collected in the range of 1.20 °≤2 θ≤25.38 °, wherein independently Point diffraction 5230.The data being collected into are through the Lp factors and empirical absorption correction.Using direct method, and through more wheel difference Fouriers Synthesis, finds out whole hydrogen atoms.All non-hydrogen atom coordinates and its equivalent anisotropy displacement parameter are all minimum with complete matrix Square law carries out refine.
Confirm after single crystal X-ray diffraction experiment and crystal structure calculate, rope fluorine cloth Wei crystal form H3 belongs to monoclinic system, space Group P21, cell parameter:α=90.00 °, β=108.78 (3) °, γ=90.00 °; Z=2, the stoichiometric equation in an asymmetry unit is C24H35FN3O10P, molecular weight 575.52, crystalline density d=1.342g/cm3
Measure obtains the monocrystalline molecular structure ellipsoid figure of rope fluorine cloth Wei crystal form H3 as shown in fig. 7, its non-hydrogen atom coordinate number According to as shown in table 5.
The non-hydrogen atom coordinate parameters of 5 crystal form H3 of table
The powder x-ray diffraction analysis of the crystal form H3 monocrystalline of embodiment 3:
The crystal form H3 monocrystalline grind into powder that embodiment 3 is obtained, carries out powder x-ray diffraction analysis, its result to it As shown in Figure 8.Corresponding with Fig. 8, the X ray diffracting data of crystal form H3 is as shown in table 6.
The powder x-ray diffraction analysis of 6 crystal form H3 of table
According to X-ray diffraction result, the position of the diffraction maximum 20 of crystal form H3 is 5.1 °, 6.7 °, 7.1 °, 9.6 °, 15.8 °, 17.2 °, 19.3 °, 19.9 °, 20.7 °, 24.9 ° etc..
Means of differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, the results are shown in Figure 9 for it.
According to the thermogravimetric spectrogram of crystal form H3 in Fig. 9, crystal form H3 has an endothermic peak 70 in the range of 50~200 DEG C ~88 DEG C.It is 5.3% that its differential thermal spectrogram, which is shown in room temperature to weight-loss ratio in the range of 180 DEG C, is spread out in error range with Single Crystal X-ray The structure that analysis obtains is penetrated to match.
Embodiment 4:The preparation of crystal form H4 monocrystalline
0.5 gram of rope fluorine cloth Wei is mixed with 5 milliliters of hexichol ether solvents, 85~90 DEG C of formation oily mixtures is heated to, connects Be slowly cooled to room temperature with 1~3 DEG C/min of speed and at room temperature stand 72 it is small when, pass through filter take out colourless needles Crystal form H4 monocrystalline.
The measure of the crystal form H4 crystal structures of embodiment 4
It is mono- to choose the rope fluorine cloth Wei crystal form H4 that size is 0.20mm × 0.10mm × 0.10mm in the crystal that embodiment 4 obtains Crystalline substance, is placed on single crystal X-ray diffraction instrument, 6737 diffraction datas is collected in the range of 1.28 °≤2 θ≤25.39 °, wherein independently Point diffraction 6514.The data being collected into are through the Lp factors and empirical absorption correction.Using direct method, and through more wheel difference Fouriers Synthesis, finds out whole hydrogen atoms.All non-hydrogen atom coordinates and its equivalent anisotropy displacement parameter are all minimum with complete matrix Square law carries out refine.
Confirm after single crystal X-ray diffraction experiment and crystal structure calculate, rope fluorine cloth Wei crystal form H4 belongs to monoclinic system, space Group P21, cell parameter:α=90.00 °, β=116.64 (3) °, γ=90.00 °; Z=2, the stoichiometric equation in an asymmetry unit is C34H39FN3O10P, Molecular weight is 699.65, crystalline density d=1.313g/cm3
The monocrystalline molecular structure ellipsoid figure that measure obtains rope fluorine cloth Wei crystal form H4 is as shown in Figure 10, its non-hydrogen atom coordinate number According to as shown in table 7.
The non-hydrogen atom coordinate parameters of 7 crystal form H4 of table
The powder x-ray diffraction analysis of the crystal form H4 monocrystalline of embodiment 4:
The crystal form H4 monocrystalline grind into powder that embodiment 4 is obtained, carries out powder x-ray diffraction analysis, its result to it As shown in figure 11.Corresponding with Figure 11, the X ray diffracting data of crystal form H4 is as shown in table 8.
The X-ray diffraction analysis of 8 crystal form H4 powder of table
According to X-ray diffraction result, the position of 2 θ of diffraction maximum of crystal form H4 is 5.5 °, 5.6 °, 10.0 °, 10.9 °, 10.9 °, 16.6 °, 19.8 °, 20.0 °, 20.4 °, 25.0 ° etc..
Means of differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, its result is as shown in figure 12.
According to the thermogravimetric spectrogram of crystal form H4 in Figure 12, crystal form H4 has an endothermic peak to exist in the range of 50~200 DEG C 64~76 DEG C.It is 17.4% that its differential thermal spectrogram, which is shown in room temperature to weight-loss ratio in the range of 200 DEG C, is penetrated in error range with monocrystalline X The structure that line diffraction analysis obtains matches.
Test example 1
The Stability Determination of resistance to high humidity is carried out to crystal form H1, crystal form H2, crystal form H3, the crystal form H4 obtained according to embodiment 1-4, And know that the crystal form form1 and form6 of rope fluorine cloth Wei are compareed with oneself.
The sample of the various crystal forms of rope fluorine cloth Wei is uniformly spread out into cloth in open-top receptacle, thickness of sample≤5 millimeter, are placed in temperature Degree 25 ± 2 DEG C, relative humidity be 60 ± 5% constant temperature and humidity incubator in, be observed after fixed time intervals t and with starting Crystal form samples are contrasted.The results are shown in Table 9.
Stability (25 DEG C/60% relative humidity) of the 9 rope fluorine cloth Wei crystal form of table under damp condition
Crystal form When t=2 is small When t=4 is small When t=24 is small When t=72 is small
Crystal form H1 Without deliquescence Without deliquescence Without deliquescence Part deliquescence
Crystal form H2 Without deliquescence Without deliquescence Without deliquescence Without deliquescence
Crystal form H3 Without deliquescence Without deliquescence Without deliquescence Without deliquescence
Crystal form H4 Without deliquescence Without deliquescence Without deliquescence Without deliquescence
Crystal form form 1 Without deliquescence Without deliquescence Part deliquescence Deliquescence
Crystal form form 6 Without deliquescence Without deliquescence Without deliquescence Part deliquescence
Change temperature and humidity condition, same sample is placed in 40 ± 2 DEG C of temperature, relative humidity is 75 ± 5% constant temperature In constant humidity incubator, it is observed after fixed time intervals t and is contrasted with initial sample crystal form.The results are shown in Table 10.
Stability (40 DEG C/75% relative humidity) of the 10 rope fluorine cloth Wei crystal form of table under damp condition
Crystal form When t=2 is small When t=4 is small When t=24 is small When t=72 is small
Crystal form H1 Without deliquescence Without deliquescence Part deliquescence Deliquescence
Crystal form H2 Without deliquescence Without deliquescence Without deliquescence Without deliquescence
Crystal form H3 Without deliquescence Without deliquescence Without deliquescence Without deliquescence
Crystal form H4 Without deliquescence Without deliquescence Without deliquescence Without deliquescence
Crystal form form 1 Part deliquescence Deliquescence Deliquescence Deliquescence
Crystal form form 6 Without deliquescence Without deliquescence Part deliquescence Deliquescence
Test result shows that crystal form H2, crystal form H3 and crystal form H4 show less under different temperatures, damp condition Hygroscopicity, it is with good stability, solve the problems, such as that existing rope fluorine cloth Wei crystal form is easier to deliquescence.
Test example 2
Solubility test in water is carried out to crystal form H1, crystal form H2, crystal form H3, the crystal form H4 obtained according to embodiment 1-4, and The crystal form form1 and form6 for knowing rope fluorine cloth Wei with oneself are compareed.Test method is all with reference to 2010 editions two ministerial standards of Chinese Pharmacopoeia Method as defined in example is tested.Specific method is as follows:Precision weighs suitable different crystal forms rope fluorine cloth Wei, is slowly added to certain Water is measured as solvent, every strength shaking in 5 minutes 30 seconds, observes the dissolving situation in 30 minutes.Test result is shown in Table 11.
The solubility of the different crystal forms of 11 rope fluorine cloth Wei of table in water
Test result shows that crystal form H1, the solubility of crystal form H2 and crystal form H3 in water are above existing known rope fluorine Cloth Wei crystal form, solve thes problems, such as that existing rope fluorine cloth Wei crystal form solubility is bad.

Claims (4)

1. a kind of crystal form H3 of rope fluorine cloth Wei, it is characterised in that using Cu-K alpha rays, the x-ray diffractogram of powder of crystal form H3 is composed In 2 θ of the angle of diffraction at 5.1 °, 6.7 °, 7.1 °, 9.6 °, 15.8 °, 17.2 °, 19.3 °, 19.9 °, 20.7 °, 24.9 ° have spy Levy peak.
2. crystal form H3 as claimed in claim 1, it is characterised in that the differential scanning calorimetric thermogram of crystal form H3 is at 70~88 DEG C There is endothermic peak at place.
3. the preparation method of the crystal form H3 for obtaining rope fluorine cloth Wei as claimed in claim 1, it is characterised in that by rope fluorine cloth Wei is added in dibenzyl ether solvents with ethanol, is heated to 70~95 DEG C, is then cooled to 0~35 DEG C, carries out crystallization, crystallization time For 1~10 day, crystal form H3 is derived from.
4. preparation method as claimed in claim 3, it is characterised in that the rope fluorine cloth Wei presses milliliter by gram weight calculation amount with solvent The ratio for counting volume is 1: 10~1: 20;Ethanol is 1: 50~1: 10 with rope fluorine cloth Wei part by weight.
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