CN106083964B - The crystal form H2 and preparation method thereof of rope fluorine cloth Wei - Google Patents
The crystal form H2 and preparation method thereof of rope fluorine cloth Wei Download PDFInfo
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Abstract
The present invention is the divisional application of patent " crystal form and preparation method thereof of rope fluorine cloth Wei ".The crystal form H2 of rope fluorine cloth Wei of the present invention and the method for being used to prepare this crystal form.The structure and cell parameter of this rope fluorine cloth Wei novel crystal forms are all made of Advances in crystal X-ray diffraction analysis and are determined.2 θ of the crystal form H2 angle of diffraction has characteristic peak at 6.7 °, 7.0 °, 9.7 °, 19.1 °, 19.3 °, 19.8 °, 20.3 °, 24.9 °, 25.1 °, 25.6 ° etc..The crystal form of the rope fluorine cloth Wei is respectively provided with the advantages that physicochemical property is excellent, stability is good, dissolubility is good, preparation manipulation is simple.
Description
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-methyl of -4--tetrahydrofuran -2- base]-Difluoro-phenoxy-phosphoryl] amino] propionic ester, chemistry
Formula: C22H29FN3O9P four kinds of novel crystalline forms) and preparation method thereof.
Background technique
Rope fluorine cloth Wei (sofosbuvir), entitled isopropyl (2S) -2- [[[(2R, 3R, 4R, the 5R) -5- (2,4- bis- of chemistry
Oxygen pyrimidine -1- base) the fluoro- 3- hydroxy-4-methyl of -4--tetrahydrofuran -2- base]-Difluoro-phenoxy-phosphoryl] amino] propionic acid
Ester, CAS number is 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 specific proteins required for hepatitis c viral replication when individually or with other medicines being used in combination
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 drug that can be used 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 is more than 10,000,000,000 dollars, is had a vast market foreground.
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.The 6 kinds of crystal forms recorded in this document are as follows:
Crystal form Form 1, 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 form6.
Crystal form form 2 be dichloromethane solvate crystallization, powder x-ray diffraction characteristic peak be 4.9 °, 6.9 °,
9.8°,19.8°,20.6°,24.7°,26.1.Crystal form form 2 is crystallized from methylene chloride and is obtained, and is converted into crystal form when dry
form 1。
Crystal form form 3 be chloroform crystalline solvate, powder x-ray diffraction characteristic peak be 6.9 °, 9.8 °,
19.7°,20.6°,24.6°.Crystal form form 3 is crystallized from chloroform and is obtained, and is converted into crystal form form 1 when dry.
Crystal form form 4, 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 is obtained, and property is unstable, and crystal form form 1 is converted into when being separated by filtration.
Crystal form form 5, 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 is obtained, and property is unstable, and crystal form form 1 is converted into when being separated by filtration.
Crystal form form 6, powder x-ray diffraction characteristic peak be 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 discloses following two and prepares crystal form
The method of form 6 is obtained from the conversion of crystal form form 1:
1) by several days formation gelling materials under 1 powder of crystal form form humidity disposed within, by gelling material grind into powder
(its powder x-ray diffraction is identical as form 1).This powder is placed in open containers sample after 6-10 week and slowly becomes brilliant
Type form 6.
2) it will be added 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.
The crystal form of existing six kinds of ropes fluorine cloth Wei has that stability is lower, solubility is lower, production technology to some extent
The disadvantages 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 drug can largely influence the characteristic of drug, 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
The new novel crystalline form with higher stability, higher solubility and the rope fluorine cloth Wei for being easier to preparation out.
Summary of the invention
The purpose of the present invention is to provide the new rope fluorine cloth Wei crystal forms with more excellent physicochemical property, and are used to prepare
The method of these crystal forms.
The inventors of the present invention are concentrated on studies in order to solve the problem, as a result have surprisingly been discovered four kinds it is new
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 obtaining crystal form
The preparation method of H1, crystal form H2, crystal form H3 and crystal form H4.It is excellent, stable that these four novel crystalline form states are respectively provided with physicochemical property
Property it is good, dissolubility is good, preparation manipulation is simple the advantages that, in industrial production and medical applications have superiority.
The crystal form H1 that the present invention announces is existed using 2 θ of the angle of diffraction in the Alpha-ray x-ray diffractogram of powder spectrum of Cu-K
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
Contain 1: 1 hydrone in analysis confirmation crystal form H1 lattice.
Crystal form H1 of the invention has within the scope of 50-200 DEG C 65~80 in DSC figure (differential scanning calorimetry figure)
Biggish endothermic peak at lesser endothermic peak and 95~110 DEG C at DEG C (its peak temperature is 100.6 DEG C).
The preparation method of present invention offer 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, the crystallization time is 1~10 day, thus to obtain the crystal form H1 of colourless needles.
It is used to prepare in the method for crystal form H1 in of the invention, methyl phenyl ethers anisole is 3 with the volume ratio of butyl oxide or isopropyl ether:
1~1: 1, preferably 1: 1；Rope fluorine cloth Wei weight (g) and the ratio of mixed solvent volume (mL) are 1: 5~1: 20, more preferably 1
:10；Water and rope fluorine cloth Wei weight ratio are 1: 100~1: 20, more preferably 3: 100；Heating 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.
Crystal form H2 of the invention using 2 θ of the angle of diffraction in 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 lattice and contains 1: 1 methanol solvate molecule.
Crystal form H2 of the invention has a suction at 84~100 DEG C in DSC figure in the range of 50~200 DEG C
Thermal spike, peak temperature are 89.1 DEG C.
The preparation method of present invention offer 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 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, thus to obtain the crystal form H2 of colourless needles.
It is used to prepare in the method for crystal form H2 in of the invention, the volume ratio of phenylene dimethyl ether and butyl oxide or isopropyl ether
It is 3: 1~1: 1, more preferably 1: 1；Rope fluorine cloth Wei weight (g) and the ratio of solvent volume (mL) are 1: 5~1: 20, preferably 1
:8；Methanol and rope fluorine cloth Wei weight ratio are 1: 20~3: 20, more preferably 1: 10；Heating 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.
Crystal form H3 of the invention using 2 θ of the angle of diffraction in 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
Contain 1: 1 alcohol solvent molecule in analysis confirmation crystal form H3 lattice
Crystal form H3 of the invention has the endothermic peak at 70~88 DEG C in DSC figure in the range of 50~200 DEG C,
Peak temperature is 74.4 DEG C.Crystal form H3 of the 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 ethyl alcohol are added in dibenzyl ether solvents, heating
To 70~95 DEG C, it is then cooled to 0~35 DEG C, carries out crystallization, the crystallization time is 1~10 day, thus to obtain the crystalline substance of colorless plate
Type H3.
It is used to prepare in the method for crystal form H3 in of the invention, the ratio of rope fluorine cloth Wei weight (g) and solvent volume (mL)
It is 1: 10~1: 20, preferably 1: 10；Ethyl alcohol and rope fluorine cloth Wei weight ratio are 1: 50~1: 10, preferably 1: 20；Heating temperature
Preferably 85~90 DEG C of degree；It is preferred that being cooled to 20~25 DEG C；The crystallization time is preferably 3 days.
Crystal form H4 of the invention using 2 θ of the angle of diffraction in 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 the diphenyl ether solvent molecule in crystal form H4 lattice containing 1: 1.
Crystal form H4 of the invention has a heat absorption at 64~76 DEG C in DSC figure 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, it is then cooled to 0~35 DEG C, carries out crystallization, the crystallization time is 1~10 day, thus to obtain the crystal form H4 of colourless needles.
It is used to prepare in the method for crystal form H4 in of the invention, the ratio of rope fluorine cloth Wei weight (g) and solvent volume (mL)
It is 1: 3~1: 20, preferably 1: 10；Heating temperature is preferably 85~90 DEG C；It is preferred that being cooled to 20~25 DEG C；The crystallization time is preferred
It is 3 days.
Detailed description of the invention
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.
Specific embodiment
Below 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.In the following examples, the experimental methods for specific conditions are not specified, 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 by existing literature report
The rope fluorine cloth Wei (J.Med.Chem.2010,53:7202-7218) of preparation；Other solvents and reagent use commercially available chemistry 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 company
CAD4/PC single crystal X-ray diffraction instrument, test temperature are 293 (2) K.With graphite monochromatised MoK alpha rayMake
Structure elucidation and amendment are carried out with SHELXS-97 (Sheldrick, 1990) and SHELXL-97 (Sheldrick, 1997).It uses
Program ORTEP obtains monocrystalline molecular structure ellipsoid figure (Fig. 1, Fig. 4, Fig. 7, Figure 10).
Cell parameter obtained by crystal structure determination has following meanings:
A, b, c are the side length 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 that PANalytical company X ' pert PRO type X is penetrated
Line powder diffractometer.Using Cu-K alpha ray, measured power is 40kV × 250mA, and scanning speed is 5 °/minute, scanning range 4
~80 ° (2 θ) of θ -2 θ continuous scanning.
In the obtained X-ray powder diffraction figure of the embodiment of the present invention (Fig. 2, Fig. 5, Fig. 8, Figure 11), horizontal axis is 2 θ of diffraction maximum
Position (unit: degree)；The longitudinal axis is diffraction peak intensity.
The weight of differential scanning amount hot-hot used in the embodiment of the present invention (DSC-TGA) analysis determining instrument is Mettler
The 1 type synchronous solving of TGA/DSC of Toledo company.Measurement range is 25~350 DEG C, and heating rate is 10 DEG C/min,
Using nitrogen protection.
In the obtained differential scanning amount hot-hot weight (DSC-TGA) figure (Fig. 3, Fig. 6, Fig. 9, Figure 12) of the embodiment of the present invention, heat
Weight (TGA) figure and calorimetric (DSC) figure are to indicate side by side up and down.Wherein horizontal axis is temperature (DEG C) in thermal multigraph, and the longitudinal axis is quality (milli
Gram), horizontal axis is temperature (unit: DEG C) in calorimetric figure, and 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 simultaneously stands 72 hours at room temperature, and the crystal form H1 monocrystalline for the colourless needles being precipitated is taken out by filtering.
Optionally, 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 measurement of the x-ray structure of crystal form H1 monocrystalline in embodiment 1.
It chooses mono- having a size of 0.30mm × 0.20mm × 0.10mm rope fluorine cloth Wei crystal form H1 in the crystal that embodiment 1 obtains
Crystalline substance is placed on single crystal X-ray diffraction instrument, and 5532 diffraction datas are collected within the scope of 1.20 °≤2 θ≤25.42 °, wherein independent
Point diffraction 5310.The data being collected into are through the Lp factor 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 all use complete matrix minimum
Square law carries out refine.
Confirm after single crystal X-ray diffraction test 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 are C22H31FN3O10P,
Molecular weight is 547.47, crystalline density d=1.251g/cm3.Measurement 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, result to it
As shown in Figure 2.The X ray diffracting data of crystal form H1 corresponding to Fig. 2 is as shown in table 2.
The powder x-ray diffraction analysis of 2 crystal form H1 of table
According to X-ray diffraction result it is found that the position of 2 θ of characteristic diffraction peak of crystal form H1 be 4.9 °, 6.6 °, 7.1 °,
8.2 °, 9.6 °, 16.5 °, 19.0 °, 19.2 °, 19.9 °, 24.9 ° etc..
Differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, result is as shown in Figure 3.
As can be seen from FIG. 3, crystal form H1 has smaller at 65~80 DEG C in thermogravimetric spectrogram within the scope of 50~200 DEG C
Endothermic peak and 95~110 DEG C at biggish endothermic peak.Its differential thermal spectrogram is shown in room temperature to weight-loss ratio within the scope 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, and is then slowly cooled to room temperature with 1~3 DEG C/min of speed and is stood 24~72 hours at room temperature, led to
The crystal form H2 of colourless needles is taken out in filtering.
Optionally, 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 measurement of crystal form H2 crystal structure in embodiment 2.
It chooses mono- having a size of 0.20mm × 0.10mm × 0.10mm rope fluorine cloth Wei crystal form H2 in the crystal that embodiment 2 obtains
Crystalline substance is placed on single crystal X-ray diffraction instrument, and 5446 diffraction datas are collected within the scope of 1.21 °≤2 θ≤25.40 °, wherein independent
Point diffraction 5216.The data being collected into are through the Lp factor 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 all use complete matrix minimum
Square law carries out refine.
Confirm after single crystal X-ray diffraction test 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 are C23H33FN3O10P,
Molecular weight is 561.49, crystalline density d=1.313g/cm3。
Measurement 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, 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 it is found that the position of 2 θ of characteristic diffraction peak of crystal form H2 be 6.7 °, 7.0 °, 9.7 °,
19.1 °, 19.3 °, 19.8 °, 20.3 °, 24.9 °, 25.1 °, 25.6 ° etc..
Differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, result is as shown in Figure 6.
As can be seen from FIG. 6, crystal form H2 has an endothermic peak in 84-100 in thermogravimetric spectrogram within the scope of 50-200 DEG C
℃.It is 5.5% that its differential thermal spectrogram, which is shown in room temperature to weight-loss ratio within the scope 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 ethyl alcohol 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 stands 72 hours at room temperature,
The crystal form H3 monocrystalline for the colourless needles being precipitated is taken out by filtering.
The measurement of the crystal form H3 crystal structure of embodiment 3
It chooses mono- having a size of 0.30mm × 0.20mm × 0.10mm rope fluorine cloth Wei crystal form H3 in the crystal that embodiment 3 obtains
Crystalline substance is placed on single crystal X-ray diffraction instrument, and 5460 diffraction datas are collected within the scope of 1.20 °≤2 θ≤25.38 °, wherein independent
Point diffraction 5230.The data being collected into are through the Lp factor 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 all use complete matrix minimum
Square law carries out refine.
Confirm after single crystal X-ray diffraction test 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 are C24H35FN3O10P,
Molecular weight is 575.52, crystalline density d=1.342g/cm3。
Measurement 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, 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 it is found that the position of 2 θ of diffraction maximum of crystal form H3 be 5.1 °, 6.7 °, 7.1 °, 9.6 °,
15.8 °, 17.2 °, 19.3 °, 19.9 °, 20.7 °, 24.9 ° etc..
Differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, result is as shown in Figure 9.
According to the thermogravimetric spectrogram of crystal form H3 in Fig. 9 it is found that crystal form H3 has an endothermic peak 70 within the scope 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 within the scope 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 hours, pass through filtering take out colourless needles
Crystal form H4 monocrystalline.
The measurement of the crystal form H4 crystal structure of embodiment 4
It chooses mono- having a size of 0.20mm × 0.10mm × 0.10mm rope fluorine cloth Wei crystal form H4 in the crystal that embodiment 4 obtains
Crystalline substance is placed on single crystal X-ray diffraction instrument, and 6737 diffraction datas are collected within the scope of 1.28 °≤2 θ≤25.39 °, wherein independent
Point diffraction 6514.The data being collected into are through the Lp factor 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 all use complete matrix minimum
Square law carries out refine.
Confirm after single crystal X-ray diffraction test and crystal structure calculate, rope fluorine cloth Wei crystal form H4 belongs to monoclinic system, space
Group P21, cell parameter:α=90.00 °, p=116.64
(3) °, γ=90.00 °； Z=2, the stoichiometric equation in an asymmetry unit are C34H39FN3O10P,
Molecular weight is 699.65, crystalline density d=1.313g/cm3。
The monocrystalline molecular structure ellipsoid figure that measurement obtains rope fluorine cloth Wei crystal form H4 is as shown in Figure 10, 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, 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 it is found that the position of 2 θ of diffraction maximum of crystal form H4 be 5.5 °, 5.6 °, 10.0 °, 10.9 °,
10.9 °, 16.6 °, 19.8 °, 20.0 °, 20.4 °, 25.0 ° etc..
Differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, result is as shown in figure 12.
According to the thermogravimetric spectrogram of crystal form H4 in Figure 12 it is found that crystal form H4 has an endothermic peak to exist within the scope 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 within the scope 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 the crystal form H1, crystal form H2, crystal form H3, the crystal form H4 that are obtained according to embodiment 1-4,
And it is compareed with the crystal form form1 and form6 of known rope fluorine cloth Wei.
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 compare.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 | T=2 hours | T=4 hours | T=24 hours | T=72 hours |
| Crystal form H1 | Without deliquescence | Without deliquescence | Without deliquescence | Part deliquesces |
| 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 deliquesces | It deliquesces |
| Crystal form form 6 | Without deliquescence | Without deliquescence | Without deliquescence | Part deliquesces |
Change temperature and humidity condition, same sample is placed in 40 ± 2 DEG C of temperature, the constant temperature that relative humidity is 75 ± 5%
In constant humidity incubator, it is observed after fixed time intervals t and is compared 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 | T=2 hours | T=4 hours | T=24 hours | T=72 hours |
| Crystal form H1 | Without deliquescence | Without deliquescence | Part deliquesces | It deliquesces |
| 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 deliquesces | It deliquesces | It deliquesces | It deliquesces |
| Crystal form form 6 | Without deliquescence | Without deliquescence | Part deliquesces | It deliquesces |
It is lesser that test result shows that crystal form H2, crystal form H3 and crystal form H4 are shown 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 deliquesce.
Test example 2
Solubility test in water is carried out to the crystal form H1, crystal form H2, crystal form H3, the crystal form H4 that are obtained according to embodiment 1-4, and
It is compareed with the crystal form form1 and form6 of known rope fluorine cloth Wei.Test method is all referring to 2010 editions two ministerial standards of Chinese Pharmacopoeia
Method as defined in example is tested.The specific method is as follows: precision weighs suitable different crystal forms rope fluorine cloth Wei, is slowly added to certain
Measure dissolution situation of the water as solvent, in strength shaking in 5 minutes 30 seconds, observation 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 efficiently solves the problems, such as that existing rope fluorine cloth Wei crystal form solubility is bad.
Claims (2)
1. a kind of crystal form H2 of rope fluorine cloth Wei, which is characterized in that use Cu-K alpha ray, the x-ray diffractogram of powder of crystal form H2 is composed
In 2 θ of the angle of diffraction have at 6.7 °, 7.0 °, 9.7 °, 19.1 °, 19.3 °, 19.8 °, 20.3 °, 24.9 °, 25.1 °, 25.6 °
Characteristic peak is prepared via a method which to obtain: rope fluorine cloth Wei and methanol are added to a phenylene dimethyl ether solvent or isophthalic diformazan
The mixed solvent of ether and butyl oxide, or the in the mixed solvent of phenylene dimethyl ether and isopropyl ether, are heated to 70 ~ 95 DEG C, then cool down
To 0 ~ 35 DEG C, crystallization is carried out, the crystallization time is 1 ~ 10 day, and thus to obtain crystal form H2, single crystal X-ray diffraction structural analysis confirmation is brilliant
Methanol solvate molecule in type H2 lattice containing 1:1；The differential scanning calorimetric thermogram of crystal form H2 has endothermic peak at 84 ~ 100 DEG C,
Peak temperature is 89.1 DEG C.
2. the crystal form H2 of rope fluorine cloth Wei as described in claim 1, which is characterized in that phenylene dimethyl ether and butyl oxide or isopropyl ether
Volume ratio be 3:1 ~ 1:1；The ratio of rope fluorine cloth Wei volume based on milliliter by gram weight calculation amount and solvent is 1:5 ~ 1:20；
Methanol and rope fluorine cloth Wei weight ratio are 1:20 ~ 3:20.
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| WO2016042576A1 (en) | 2014-09-16 | 2016-03-24 | Cadila Healthcare Limited | Co-crystal of sofosbuvir and amino acid and process for preparation thereof |
| CN105985394B (en) * | 2015-02-26 | 2020-09-22 | 石药集团中奇制药技术（石家庄）有限公司 | Novel Sofosbuvir crystal form and preparation method thereof |
| CN104829673B (en) * | 2015-03-12 | 2017-10-27 | 南京旗昌医药科技有限公司 | A kind of preparation method of rope fluorine cloth Wei crystal formation 6 |
| CN106146589B (en) * | 2015-04-10 | 2019-03-05 | 正大天晴药业集团股份有限公司 | The crystallization of deuterated nucleoside derivates |
| CN104804054B (en) * | 2015-04-17 | 2017-10-24 | 南京旗昌医药科技有限公司 | A kind of crystal formation of rope fluorine cloth Wei and its application |
| CN105017359A (en) * | 2015-07-08 | 2015-11-04 | 苏州晶云药物科技有限公司 | Preparation method of Sofosbuvir crystal form |
| WO2017158624A1 (en) * | 2016-03-17 | 2017-09-21 | Mylan Laboratories Limited | Polymorphic forms of sofosbuvir |
| CN106496295A (en) * | 2016-10-19 | 2017-03-15 | 上海博志研新药物技术有限公司 | The preparation method of Suo Feibuwei crystal formations 6 |
| CN108084237A (en) * | 2016-11-23 | 2018-05-29 | 广东东阳光药业有限公司 | Monohydrate of Suo Feibuwei and preparation method thereof |
| WO2019025600A1 (en) | 2017-08-03 | 2019-02-07 | Sandoz Ag | Sofosbuvir hydrate |
| WO2021203409A1 (en) * | 2020-04-10 | 2021-10-14 | 南京正大天晴制药有限公司 | Novel non-hygroscopic low-variability crystalline form for treatment of hepatitis c |
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| CN106188195A (en) | 2016-12-07 |
| CN106188195B (en) | 2019-03-08 |
| CN106083964A (en) | 2016-11-09 |
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| CN104447924A (en) | 2015-03-25 |
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