CN104211704B - Triazole [4,5 d] pyrimidine compound of crystal habit and its production and use - Google Patents
Triazole [4,5 d] pyrimidine compound of crystal habit and its production and use Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
Disclose formula (I) compound of a variety of crystal habits and preparation method thereof and medical usage.The compound of the different crystal habits of offer has improved one or more following properties：Crystallinity, solubility, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density.
Description
Technical field
The application is related to triazole [4,5-d] the pyrimidine chemical combination in pharmaceutical chemistry crystallization technique field, more particularly to crystal habit
Thing and its production and use.
Background technology
Triazole [4,5-d] pyrimidine compound researched and developed by Astrazeneca AB (AstraZeneca) was on July 20th, 2011
Obtain FDA approvals, the generation for reducing acute coronary syndrome (ACS) patient's Cardioversion.Triazole [4,5-d] pyrimidine
Compound is a kind of new, selective anticoagulant, is also first reversible mating type P2Y12 adenosine diphosphate acceptors
(ADP) antagonist, the receptor subtype P2Y12 of purine 2 that can reversibly on vasoactive smooth muscle cell (VSMC), to ADP
Caused platelet aggregation has an obvious inhibitory action, and it is rapid to work after being administered orally, and can effectively improve acute coronary trouble
The symptom of person.
The chemical name of triazole [4,5-d] pyrimidine compound is (1S, 2S, 3R, 5S) -3- [7- [(1R, 2S) -2- (3,4-
Difluorophenyl) cyclopropyl amino] -5- (rosickyite base) -3H- [1,2,3] triazole [4,5-d] pyrimidin-3-yl] -5- (2- '-hydroxyethoxies
Base) pentamethylene -1,2- glycol, with chemical structural formula as follows：
The crystal formation screening of triazole [4,5-d] pyrimidine compound and crystal formation technical study have important meaning to its drug development
Justice.
The four kinds of crystal formations and one kind that document WO2001/0922621A discloses triazole [4,5-d] pyrimidine compound are amorphous
Form.The preparation technology of amorphous form is generally difficult to control, and stability is compared with crystal formation and mobility is poor, is unsuitable for preparation
Using.Its content is hereby incorporated by reference by the application.
Document CN1432018A (WO2001/0922621A) discloses the anhydrous crystal forms of triazole [4,5-d] pyrimidine compound
I, II, III and IV, it is believed that these anhydrous crystal forms have the advantage that in pharmaceutical composition is prepared, and can simplify processing and handle.This
Its content is hereby incorporated by reference by application.Patent document WO2001/092262A describes triazole [4,5-d] pyrimidine chemical combination
Crystal formation I, II, III and IV of thing.
Described in document CN1432018A, anhydrous crystal forms I has following characteristic peak in X-ray diffractogram：5.3 °,
8.0 °, 9.6 °, 13.9 °, 15.3 °, 20.1 °, 20.7 °, 21.0 °, 21.3 °, 26.2 ° and 27.5 ° ± 0.2 ° of 2 θ, are high-temperature stables
Form, is obtained by way of being cooled down after crystal formation II is heated in DSC.Also it can mix molten in methanol/water under the conditions of 30 DEG C
In liquid, plus the brilliant mode of crystal formation I crystal seeds length is obtained.
Crystal formation II has following characteristic peak in X-ray diffractogram：5.5 °, 6.8 °, 10.6 °, 13.5 °, 14.9 °,
18.3 °, 19.2 °, 22.7 °, 24.3 ° and 27.1 ° ± 0.2 ° of 2 θ, can be obtained in chloroformic solution by way of volatilization.
Crystal formation III has following characteristic peak in X-ray diffractogram：5.6 °, 12.5 °, 14.0 °, 17.4 °, 18.4 °,
21.4 °, 22.2 °, 22.9 °, 24.1 ° and 24.5 ° ± 0.2 ° of 2 θ.
Crystal formation II and crystal formation III mixture can be made in volatilization after being dissolved by heating in ethanol solution.
By crystal formation II in aqueous isopropanol magma, can after magma while the mixture for adding above-mentioned II/III is crystal seed
Obtain pure crystal formation III.
Cooled down after triazole [4,5-d] pyrimidine compound is dissolved by heating in acetonitrile, nitrogen drying crystallization can obtain crystal formation IV.
Crystal formation IV in X-ray diffractogram have following 4.9 ° of characteristic peak, 6.0 °, 9.2 °, 11.6 °, 12.8 °, 15.6 °, 16.4 °,
17.2 ° and 18.1 ° of ± 0.2 ° of 2 θ.
Rotated after triazole [4,5-d] pyrimidine compound is dissolved in the aqueous solution of 50% ethanol, amorphous form can be obtained.
By CN1432018A description, in crystal formation I, II, III and IV, at normal temperatures, II is metastable state, suitable
Crystal formation I or III can be converted under the conditions of.
Although the feature X that triazole [4,5-d] pyrimidine compound crystal formation I, II, III and IV are given in CN1432018A is penetrated
Line powder diffraction spectrum and DSC curve figure, but do not provide the mutual transforming relationship of each crystal formation.In addition, crystal formation I, II,
III and IV are very difficultly soluble in water, this solubility to medicine, and dissolution rate or even bioavilability are all a challenges.Though
The right common solubility of amorphous substance can be better than amorphous material, but amorphous substance has and is difficult to purify, easy moisture absorption, flowing
The characteristics such as difference, are unfavorable for industrial production and use.
Therefore, this area needs to develop new triazole [4,5-d] pyrimidine compound crystal formation, and the crystal formation will possess good pure
Degree, higher solubility and the features such as suitable for formulation application.
New anhydrous crystal forms and solvate can provide the material with more preferable physicochemical property, such as disposable, technique
It is more simplified, or it is more conducive to the intermediate state crystal formation to most steady transformation of crystal.New anhydrous crystal forms and solvate can also be carried
For a chance for improving drug products performance.More triazoles [4,5-d] pyrimidine compound is prepared it would therefore be desirable to develop
Novel crystal forms.
General introduction
On the one hand there is provided the formula of crystal habit (I) compound,
Wherein, the compound has following crystal formation：
Crystal formation 1, being characterized in 5.2 °, 9.0 °, 9.5 °, 10.0 °, 10.3 °, 12.3 ° and 20.7 ° ± 0.2 ° of 2 θ through XRD has
High intensity peak；
Crystal formation 2, being characterized in 5.2 °, 9.6 °, 10.7 °, 14.9 °, 17.5 ° and 19.4 ° ± 0.2 ° of 2 θ through XRD has high intensity
Peak；
Crystal formation 3, being characterized in 5.1 °, 9.5 °, 10.7 °, 19.6 °, 20.3 ° and 21.2 ° ± 0.2 ° of 2 θ through XRD has high intensity
Peak；
Crystal formation 4, being characterized in 5.3 °, 10.5 ° and 21.0 ° ± 0.2 ° of 2 θ through XRD has high intensity peak；
Crystal formation 5, through XRD be characterized in 5.1 °, 10.2 °, 15.2 °, 17.3 °, 19.7 ° and 20.3 ° ± 0.2 ° of 2 θ have it is high-strength
Spend peak；
Crystal formation 6, being characterized in 5.1 °, 9.5 °, 10.7 °, 13.8 °, 14.8 ° and 19.9 ° ± 0.2 ° of 2 θ through XRD has high intensity
Peak；
Crystal formation 7, through XRD be characterized in 5.2 °, 10.8 °, 13.9 °, 14.9 °, 16.0 ° and 19.9 ° ± 0.2 ° of 2 θ have it is high-strength
Spend peak；
Crystal formation 8,5.2 ° are characterized in through XRD, 10.3 °, 13.9 °, and 20.7 ° of ± 0.2 ° of 2 θ have high intensity peak；
Crystal formation 9, being characterized in 5.1 °, 10.8 °, 13.9 °, 19.9 ° and 21.3 ° ± 0.2 ° of 2 θ through XRD has high intensity peak.
In a preferred embodiment, formula (I) compound of the crystal habit of the application is substantially pure, is more preferably had
Single crystal form.
Triazole [4,5-d] pyrimidine compound of the crystal habit of the application compares triazole [4,5-d] pyrimidine of known crystal formation
Compound has improved one or more following properties：Crystallinity, solubility, dissolution rate, particle shape, thermodynamics and machine
Tool stability, hygroscopicity, mobility, compressibility and apparent density.
On the other hand there is provided the preparation method of the formula of the application crystal habit (I) compound, including：
Raw material formula (I) compound is dissolved in suitable solvent；And
Volatilized by room temperature, slowly volatilization, magma precipitation, polymeric stencil volatilization, cooling recrystallization or anti-solvent are tied again
Crystal method makes the compound of the crystal habit be separated out from resulting solution.
In a preferred embodiment, for the crystal formation 1, the preparation method includes raw material formula (I) compound is molten
Solution is then volatilized, slowly volatilization or polymeric stencil evaporation method are obtained in suitable solvent by room temperature；
For the crystal formation 2, the preparation method includes raw material formula (I) compound being dissolved in suitable solvent, and
Volatilized afterwards by room temperature, room temperature magma is separated out or polymeric stencil evaporation method is obtained；
For the crystal formation 3, the preparation method includes raw material formula (I) compound being dissolved in dioxane solvent, and
Obtained afterwards by room temperature evaporation method；
For the crystal formation 4, the preparation method includes raw material formula (I) compound being dissolved in suitable solvent, and
Obtained afterwards by slowly volatilizing, cooling down recrystallization or polymeric stencil evaporation method；
For the crystal formation 5, the preparation method includes raw material formula (I) compound being dissolved in suitable solvent, and
Obtained afterwards by cooling down recrystallization method；
For the crystal formation 6, the preparation method includes raw material formula (I) compound being dissolved in suitable solvent, and
Obtained afterwards by cooling down recrystallization method；
For the crystal formation 7, the preparation method includes raw material formula (I) compound being dissolved in suitable solvent, and
Obtained afterwards by cooling down recrystallization or anti-solvent recrystallization method；
For the crystal formation 8, the preparation method includes raw material formula (I) compound being dissolved in suitable solvent, and
Obtained afterwards by slow evaporation method；And
For the crystal formation 9, the preparation method includes raw material formula (I) compound being dissolved in suitable solvent, and
Obtained afterwards by room temperature magma separation method.
Compared with prior art, the method for triazole [4, the 5-d] pyrimidine compound for the crystal habit that the application is provided has
Advantages below：Preparation technology is easy, and reaction condition is gentle.Without reacting the long period under the high temperature conditions.Only need to be in room temperature bar
Crystallization can obtain required crystal formation, therefore simple production process under part, and production cost is relatively low.
Another further aspect includes the formula (I) of crystal habit that provides of the application of effective dose there is provided a kind of pharmaceutical composition
Compound and pharmaceutically acceptable excipient.
In some embodiments, described pharmaceutical composition can be used for treat or prevent with coronary artery, the cerebrovascular or
The Arterial thrombosis complication of the patient of peripheral artery disease.
In some embodiments, described pharmaceutical composition can be used for the growth and diffusion of pre- preventing tumor.
Another further aspect has there is provided the formula of the crystal habit of the application (I) compound in preparation for treatment or prevention
Purposes in the medicine of the Arterial thrombosis complication of the patient of coronary artery, the cerebrovascular or peripheral artery disease.
Another further aspect there is provided the formula of the application crystal habit (I) compound prepare for pre- preventing tumor growth and
Purposes in the medicine of diffusion.
There is provided treat or prevent the dynamic of the patient with coronary artery, the cerebrovascular or peripheral artery disease for another aspect
The method of arteries and veins thrombosis complication, including give the formula of the application crystal habit of patient in need's therapeutically effective amount
(I) the application pharmaceutical composition of compound or therapeutically effective amount.
Another further aspect is there is provided the method for the growth of pre- preventing tumor and diffusion, including gives patient in need treatment
Formula (I) compound or the application pharmaceutical composition of therapeutically effective amount of the application crystal habit of effective dose.
Brief description of the drawings
Fig. 1 shows the XRPD figures of the crystal formation 1 of triazole [4,5-d] pyrimidine compound.
Fig. 2 shows the DSC figures of the crystal formation 1 of triazole [4,5-d] pyrimidine compound.
Fig. 3 shows the XRPD figures of the crystal formation 2 of triazole [4,5-d] pyrimidine compound.
Fig. 4 shows the TGA figures of the crystal formation 2 of triazole [4,5-d] pyrimidine compound.
Fig. 5 shows the DSC figures of the crystal formation 2 of triazole [4,5-d] pyrimidine compound.
Fig. 6 shows the dynamic moisture content absorption figure of the crystal formation 2 of triazole [4,5-d] pyrimidine compound.
Fig. 7 shows the isothermal adsorption figure of the crystal formation 2 of triazole [4,5-d] pyrimidine compound.
Fig. 8 shows the XRPD figures of the crystal formation 3 of triazole [4,5-d] pyrimidine compound.
Fig. 9 shows the XRPD figures of the crystal formation 4 of triazole [4,5-d] pyrimidine compound.
Figure 10 shows the TGA figures of the crystal formation 4 of triazole [4,5-d] pyrimidine compound.
Figure 11 shows the DSC figures of the crystal formation 4 of triazole [4,5-d] pyrimidine compound.
Figure 12 shows the dynamic moisture content absorption figure of the crystal formation 4 of triazole [4,5-d] pyrimidine compound.
Figure 13 shows the isothermal adsorption figure of the crystal formation 4 of triazole [4,5-d] pyrimidine compound.
Figure 14 shows the XRPD figures of the crystal formation 5 of triazole [4,5-d] pyrimidine compound.
Figure 15 shows the DSC figures of the crystal formation 5 of triazole [4,5-d] pyrimidine compound.
Figure 16 shows the XRPD figures of the crystal formation 6 of triazole [4,5-d] pyrimidine compound.
Figure 17 shows the XRPD figures of the crystal formation 7 of triazole [4,5-d] pyrimidine compound.
Figure 18 shows the XRPD figures of the crystal formation 8 of triazole [4,5-d] pyrimidine compound.
Figure 19 shows the XRPD figures of macromolecule polyacrylic acid (PAA).
Figure 20 shows TGA the and DSC overlay charts of macromolecule polyacrylic acid (PAA).
Figure 21 shows the XRPD figures of polyphosphazene polymer allylamine hydrochloride (PAH).
Figure 22 shows TGA the and DSC overlay charts of polyphosphazene polymer allylamine hydrochloride (PAH).
Figure 23 shows the XRPD figures of PDDA (PDADMAC).
Figure 24 shows the TGA/DSC figures of PDDA (PDADMAC).
Figure 25 shows the XRPD figures of the crystal formation 9 of triazole [4,5-d] pyrimidine compound.
Figure 26 shows the DSC figures of the crystal formation 9 of triazole [4,5-d] pyrimidine compound.
Embodiment
In a first aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 1.The DSC figures of the crystal formation show that fusing point is 148 DEG C.
The representational X-ray powder diffraction figure of triazole [4,5-d] pyrimidine compound crystal formation 1 is as shown in Figure 1.The crystal formation exists
5.2 °, 9.0 °, 9.5 °, 10.0 °, 10.3 °, 12.3 ° and 20.7 ° ± 0.2 ° of 2 θ have characteristic peak；Or at 5.2 °, 9.0 °,
9.5 °, 10.0 °, 10.3 °, 12.3,13.8 °, 16.6 °, 20.7 °, 21.1 °, 22.0 °, 25.9 ° and 31.3 ° ± 0.2 ° of 2 θ have spy
Levy peak.
The representational DSC figures of triazole [4,5-d] the pyrimidine compound crystal formation 1 of the application are as shown in Figure 2.
Triazole [4,5-d] the pyrimidine compound crystal formation 1 has improved one or more following properties：It is crystallinity, molten
Xie Du, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density, it is special
It is not at least one following aspect：Chemical purity, pattern and solubility.
Triazole [4,5-d] the pyrimidine compound crystal formation 1 can be volatilized in suitable dicyandiamide solution by room temperature to ease up
Slow vaporization method is obtained, and can also be obtained by polymeric stencil evaporation method.Adoptable solvent includes ketone such as MEK, alcohol
Class such as methanol, ethanol and 2- butanol, and other solvents such as ether solvent such as dioxane and tetrahydrofuran.Selectively, to
Addition is not more than the polymer substance of the mass ratio of compound 5% in gained triazole [4,5-d] pyrimidine compound solution, described
Polymer substance is preferably selected from polyacrylic acid PDDA, polymethyl methacrylate, PAH
Hydrochloride and polyacrylic acid.The XRPD figures of crystal formation 1 are obtained when sample is also no completely dry, may now be contained in sample
A small amount of residual solvent.
Because the macromolecule used in this application is amorphous substance, and DSC does not show fusing point, along with
High molecular consumption is less than the 5% of triazole [4,5-d] pyrimidine compound quality in the feeding intake of crystallization experiment, it is believed that a small amount of
Polymer substance will not judge last crystal formation to produce influence.When crystal formation 1, same XRD spectrum is present in not
Plus high molecular room temperature is volatilized and added in high molecular room temperature volatilization, it was demonstrated that macromolecule judges crystal formation not influence.
Second aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 2.The DSC figures of the crystal formation show that fusing point is 153.5 DEG C.
The representational X-ray powder diffraction figure of the application triazole [4,5-d] pyrimidine compound crystal formation 2 is as shown in Figure 3.Should
Crystal formation has characteristic peak in 5.2 °, 9.6 °, 10.7 °, 14.9 °, 17.5 ° and 19.4 ° ± 0.2 ° of 2 θ；Or at 5.2 °, 9.6 °,
10.7 °, 14.9 °, 15.7 °, 17.5 °, 19.4 °, 20.7 °, 21.2 °, 21.5 °, 22.4 °, and 25.6 ° of ± 0.2 ° of 2 θ have feature
Peak.
The representational TGA figures of triazole [4,5-d] the pyrimidine compound crystal formation 2 of the application are as shown in Figure 4.In TGA figures,
Crystal formation 2 shows that sample is 1.2% in 150 DEG C of weightlessness under 10 DEG C/min heating condition, is losing for surface solvent, crystal formation 2 is
Anhydrous crystal forms.
The representational DSC figures of triazole [4,5-d] the pyrimidine compound crystal formation 2 of the application are as shown in Figure 5.In DSC figures,
Crystal formation 2 shows fusing point about at 153.5 DEG C or so under 10 DEG C/min heating condition.
Representational dynamic moisture content the absorption figure such as Fig. 6 and Fig. 7 of triazole [4,5-d] the pyrimidine compound crystal formation 2 of the application
It is shown.Fig. 6 and Fig. 7 shows that the sample of crystal formation 2 is substantially non-hygroscopic below the condition of 80% relative humidity.
Triazole [4,5-d] the pyrimidine compound crystal formation 2 can be volatilized in suitable dicyandiamide solution by room temperature, room temperature is brilliant
Slurry is separated out and polymeric stencil evaporation method is obtained.These methods generally include triazole [4,5-d] pyrimidine compound being dissolved in
In one or two kinds of following organic solvents：Chloroform, MEK, isopropyl ether, pyridine, dioxanes, tetrahydrofuran and alcohols such as first
Alcohol, ethanol and normal propyl alcohol etc..
Triazole [4,5-d] the pyrimidine compound crystal formation 2 has improved one or more following properties：It is crystallinity, molten
Xie Du, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density, it is special
It is not at least one following aspect：Chemical purity, pattern and solubility.Especially specifically, crystal formation 2 has good pattern
Feature, such as crystal formation 2 have less granularity, and this is favourable in some cases, such as improves compressibility.
The third aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 3.
The representational X-ray powder diffraction figure of the application triazole [4,5-d] pyrimidine compound crystal formation 3 is as shown in Figure 8.Should
Crystal formation has characteristic peak in 5.1 °, 9.5 °, 10.7 °, 19.6 °, 20.3 ° and 21.2 ° ± 0.2 ° of 2 θ；Or at 4.8 °, 5.1 °,
9.5 °, 10.7 °, 19.6 °, 20.3 °, 20.5 °, 21.2 °, 21.8 ° and 22.5 ° ± 0.2 ° of 2 θ have characteristic peak.
Triazole [4,5-d] the pyrimidine compound crystal formation 3 can be in triazole [4,5-d] pyrimidine compound dioxane solvents
Obtained by room temperature evaporation method.Crystal formation 3 is detected in not by dry sample.
Triazole [4,5-d] the pyrimidine compound crystal formation 3 is hydrate.
The advantage of triazole [4,5-d] the pyrimidine compound crystal formation 3 is that itself is easy to get very much, it is not necessary to which fusing sample is logical
Cross magma precipitation.
Triazole [4,5-d] the pyrimidine compound crystal formation 3 has improved one or more following properties：It is crystallinity, molten
Xie Du, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density.
Fourth aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 4.The DSC figures of the crystal formation show that fusing point is 150.0 DEG C.
The representational X-ray powder diffraction figure of triazole [4,5-d] the pyrimidine compound crystal formation 4 of the application is as shown in Figure 9.
The crystal formation has characteristic peak in 5.3 °, 10.5 ° and 21.0 ° ± 0.2 ° of 2 θ；Or at 5.3 °, 5.6 °, 10.5 °, 21.0 °, 26.3 °
There is characteristic peak with 31.7 ± 0.2 ° of 2 θ.
Triazole [4,5-d] the pyrimidine compound crystal formation 4 is anhydride.
The representational TGA figures of triazole [4,5-d] the pyrimidine compound crystal formation 4 of the application are as shown in Figure 10.TGA displays are brilliant
Type 4 has 0.6% weightlessness at 150 DEG C, and it is anhydrous to show crystal formation 4.
The representational DSC figures of triazole [4,5-d] the pyrimidine compound crystal formation 4 of the application are as shown in figure 11.The figure shows,
Under 10 DEG C/min of heating condition, crystal formation 4 has individual melting peak at 150 DEG C or so.The figure shows that the melting peak of sample seems
It is formed by stacking by two peaks, shows that crystal phenomenon can occur during heating for crystal formation 4.
Representational dynamic moisture content the absorption figure such as Figure 12 and figure of triazole [4,5-d] the pyrimidine compound crystal formation 4 of the application
Shown in 13.Shown adsorption curve shows that the sample of crystal formation 4 only absorbs 0.8% moisture content under conditions of 80%RH.
Triazole [4,5-d] the pyrimidine compound crystal formation 4 can be by triazole [4,5-d] pyrimidine compound is in organic solvent or has
In machine solvent and water mixed system, or in the mixed system of organic solvent by cooling be recrystallized to give.The organic solvent choosing
From methanol, ethanol, normal propyl alcohol, ethyl methyl ether and acetone etc..The crystal formation 4 can also be from normal propyl alcohol by slowly volatilizing or high score
Submodule version volatilization is obtained.Crystal formation 4 also can be dried at room temperature for obtaining by crystal formation 5,6,7 and 8.Condition of the crystal formation 4 in 40 DEG C of heating
Under can be converted into crystal formation I.
Triazole [4,5-d] the pyrimidine compound crystal formation 4 has improved one or more following properties：It is crystallinity, molten
Xie Du, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density, it is special
It is not in terms of hygroscopicity.Because crystal formation 4 relative to crystal formation I is metastable state, this also illustrates crystal formation 4 in solubility compared with crystal formation I
It is advantageous.
5th aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 5.The DSC figures of the crystal formation show that fusing point is 150.0 DEG C.
Representational X-ray powder diffraction figure such as Figure 14 institutes of triazole [4,5-d] the pyrimidine compound crystal formation 5 of the application
Show.The crystal formation has characteristic peak in 5.1 °, 10.2 °, 15.2 °, 17.3 °, 19.7 ° and 20.3 ° 2 θ；Or at 5.1 °, 10.2 °,
14.8 °, 15.2 °, 15.9 °, 17.3 °, 19.7 °, 20.3 °, 21.9 °, 24.1 °, 25.5 ° and 30.7 ° ± 0.2 ° of 2 θ have characteristic peak.
The representational DSC figures of triazole [4,5-d] the pyrimidine compound crystal formation 5 of the application are as shown in figure 15.The figure shows,
Under 10 DEG C/min of heating condition, crystal formation 5 has individual melting peak after solvent is lost at 150 DEG C or so.
Triazole [4,5-d] the pyrimidine compound crystal formation 5 can be by triazole [4,5-d] pyrimidine compound in organic solvent and water
In mixed system, or in the mixed system of organic solvent by cooling be recrystallized to give.Preferably, solvent for use is second alcohol and water
Mixed solvent system.Crystal formation 5 is detected in the wet sample of above-mentioned system.Crystal formation 5 is alcohol solvent compound.
Triazole [4,5-d] the pyrimidine compound crystal formation 5 has improved one or more following properties：It is crystallinity, molten
Xie Du, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density.
6th aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 6.
Representational X-ray powder diffraction figure such as Figure 16 institutes of triazole [4,5-d] the pyrimidine compound crystal formation 6 of the application
Show.The crystal formation has characteristic peak in 5.1 °, 9.5 °, 10.7 °, 13.8 °, 14.8 ° and 19.9 ° ± 0.2 ° of 2 θ；Or at 5.1 °,
9.5 °, 10.1 °, 10.7 °, 13.8 °, 14.8 °, 16.0 °, 19.9 °, 20.3 °, 21.3 °, 22.4 ° and 30.6 ° ± 0.2 ° of 2 θ have spy
Levy peak.
Triazole [4,5-d] the pyrimidine compound crystal formation 6 of the application can by triazole [4,5-d] pyrimidine compound acetone with
It is recrystallized to give in water, or the mixed system of tetrahydrofuran and water by cooling.Crystal formation 6 is detected in the wet sample of above-mentioned system
In, crystal formation 6 is hydrate.It is just like Figure 16 XRPD2 θ characteristic peaks.
The crystal formation 6 of triazole [4,5-d] pyrimidine compound has improved one or more following properties：Crystallinity,
Solubility, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density.
7th aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 7.
Representational X-ray powder diffraction figure such as Figure 17 institutes of triazole [4,5-d] the pyrimidine compound crystal formation 7 of the application
Show.The crystal formation has characteristic peak in 5.2 °, 10.8 °, 13.9 °, 14.9 °, 16.0 ° and 19.9 ° ± 0.2 ° of 2 θ；Or at 5.2 °,
9.6 °, 10.8 °, 13.9 °, 14.9 °, 16.0 °, 19.9 °, 20.5 °, 21.3 °, 21.6 °, 22.5 ° and 25.7 ° ± 0.2 ° of 2 θ have spy
Levy peak.
Triazole [4,5-d] the pyrimidine compound crystal formation 7 of the application can be by triazole [4,5-d] pyrimidine compound in first alcohol and water
Recrystallized, or be recrystallized to give in methanol and water mixed system by anti-solvent by cooling down in mixed system.Crystal formation 7 is rarely seen
In the wet sample of above-mentioned system.Crystal formation 7 is Methanol Solvate.
Triazole [4,5-d] the pyrimidine compound crystal formation 7 has improved one or more following properties：It is crystallinity, molten
Xie Du, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density.
Eighth aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 8.
Representational X-ray powder diffraction figure such as Figure 18 institutes of triazole [4,5-d] the pyrimidine compound crystal formation 8 of the application
Show.The crystal formation is at 5.2 °, 10.3 °, 13.9 °, and 20.7 ° of ± 0.2 ° of 2 θ have characteristic peak；Or at 5.2 °, 5.5 °, 10.3 °,
13.9 °, 18.3 °, 20.7 °, 26.0 ° and 31.2 ° ± 0.2 ° of 2 θ have characteristic peak.
Triazole [4,5-d] the pyrimidine compound crystal formation 8 of the application can be by triazole [4,5-d] pyrimidine compound in normal propyl alcohol
Obtained by slow evaporation method.Crystal formation 8 is detected in the wet sample of above-mentioned system.Crystal formation 8 is normal propyl alcohol solvate.
Triazole [4,5-d] the pyrimidine compound crystal formation 8 has improved one or more following properties：It is crystallinity, molten
Xie Du, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density.
9th aspect, this application provides a kind of triazole of crystal habit [4,5-d] pyrimidine compound and preparation method thereof,
The compound has crystal formation 9.The DSC figures of the crystal formation show that fusing point is 145.1 DEG C.
Representational X-ray powder diffraction figure such as Figure 25 institutes of triazole [4,5-d] the pyrimidine compound crystal formation 9 of the application
Show.The crystal formation has characteristic peak in 5.1 °, 10.8 °, 13.9 °, 19.9 ° and 21.3 ° ± 0.2 ° of 2 θ；Or at 5.1 °, 9.6 °,
10.8 °, 13.9 °, 14.7 °, 16.0 °, 19.9 °, 21.3 °, 22.5 ° and 27.5 ° ± 0.2 ° of 2 θ have characteristic peak.
The representational DSC figures of triazole [4,5-d] the pyrimidine compound crystal formation 9 of the application are as shown in figure 26.
Triazole [4,5-d] the pyrimidine compound crystal formation 9 of the application can be passed through by triazole [4,5-d] pyrimidine compound in water
Magma separation method is obtained.
Triazole [4,5-d] the pyrimidine compound crystal formation 9 has improved one or more following properties：It is crystallinity, molten
Xie Du, dissolution rate, particle shape, thermodynamics and mechanical stability, hygroscopicity, mobility, compressibility and apparent density.
Tenth aspect, this application provides a kind of pharmaceutical composition, including formula (I) compound and medicine of crystal habit can
The excipient of receiving, wherein the crystal habit is any crystal formation in above-mentioned crystal formation 1-9.
In some embodiments, described pharmaceutical composition can be used for treat or prevent with coronary artery, the cerebrovascular or
The Arterial thrombosis complication of the patient of peripheral artery disease.
In some embodiments, described pharmaceutical composition can be used for the growth and diffusion of pre- preventing tumor.
Tenth on the one hand, has this application provides the formula of crystal habit (I) compound in preparation for treatment or prevention
Purposes in the medicine of the Arterial thrombosis complication of the patient of coronary artery, the cerebrovascular or peripheral artery disease, wherein institute
It is any crystal formation in above-mentioned crystal formation 1-9 to state crystal habit.
12nd aspect, the growth for pre- preventing tumor is being prepared this application provides the formula of crystal habit (I) compound
With the purposes in the medicine of diffusion, wherein the crystal habit be above-mentioned crystal formation 1-9 in any crystal formation.
13rd aspect, this application provides treat or prevent with coronary artery, the cerebrovascular or peripheral artery disease
The method of the Arterial thrombosis complication of patient, including give the formula of the crystal habit of the bacterium thus needed
(I) the application pharmaceutical composition of compound or therapeutically effective amount, wherein the crystal habit is any in above-mentioned crystal formation 1-9
Crystal formation.
Fourteenth aspect, this application provides the method for the growth of pre- preventing tumor and diffusion, including gives this needs
Formula (I) compound or the application pharmaceutical composition of therapeutically effective amount of the crystal habit of bacterium, wherein institute
It is any crystal formation in above-mentioned crystal formation 1-9 to state crystal habit.
In this application, term " formula (I) compound " and " triazole [4,5-d] pyrimidine compound " can be substituted for each other,
Represent triazole [4,5-d] pyrimidine compound with formula (I) structure.
In a preferred embodiment, formula (I) compound of the application crystal habit is substantially pure, more preferably with list
One crystal formation.
In this application, term " substantially pure " or substantially free represent that the triazole [4,5-d] of the crystal habit is phonetic
In acridine compound in addition to content highest oikocryst type, only other crystal formations containing less than 20% (weight), preferably less than 10% (weight
Amount) other crystal formations, other crystal formations of more preferably less than 5% (weight), other crystal formations of particularly preferably less than 1% (weight).
In some embodiments, triazole [4,5-d] pyrimidine compound of the application crystal habit contains 1% to 20% (weight
Amount), 5% to 20% (weight), or 5% to 10% (weight) other crystal formations.
In this application, term " single crystal form " refers to triazole [4,5-d] pyrimidine compound of the crystal habit and penetrated through X-
Line powder diffraction is detected as single crystal formation.
In a preferred embodiment, triazole [4,5-d] pyrimidine compound of herein described crystal habit has single
Crystal formation 1,2 or 4.
In this application, term " crystal " refer to by X-ray diffractogram characterization method confirm in crystal habit triazole [4,
5-d] pyrimidine compound.
In this application, term " crystal formation ", " polymorphic " and other relative words refer to triazole [4,5-d] pyrimidine solid chemical combination
Thing exists in crystal structure with specific crystal form state.The difference of different crystal forms physicochemical property can be embodied in stable storing
In terms of property, compressibility, density and dissolution rate.The difference of solubility or dissolution rate, in extreme situations, Ke Yizao
Into medicine is poorly efficient or even toxicity.
X-ray powder diffraction, infrared spectrum, Raman spectrum can be used as the foundation for judging compound novel crystal forms.
Different crystal formations can provide different physicochemical properties, such as fusing point.In this application, TA is passed through
The Q200MDSC of Instruments companies determines the fusing point of material.The initial temperature of fusing point is measured according to TA analysis softwares
The point of the DSC baseline significant changes arrived is determined.Fusing point can also be surveyed by other technologies, Other Instruments or other experiment conditions
It is fixed.Therefore, not necessarily one absolute numerical value of the data of fusing point here.One skilled in the art will recognize that the essence of fusing point
Exact figures value can be influenceed by the purity of compound, sample size, firing rate and granularity.
It will be appreciated by those skilled in the art that physicochemical property discussed herein can pass through existing technological means table
Levy, experimental error therein depends on the condition of instrument, the preparation of sample and sample purity.For example, it is known that X-ray diffractogram is logical
It can often change with the change of instrument condition, particularly the relative intensity of X-ray diffractogram may also be with experiment condition
Change and change, so the strong and weak order at peak is not considered generally.In addition, the experimental error of peak angle degree is generally 5% or less,
The error of these angles should generally be considered into.It is, therefore, to be understood that this application claims crystal formation actual measurement
X-ray diffractogram need not be completely the same with corresponding X-ray diffractogram given herein.It is any have and collection of illustrative plates used herein it is basic
The crystal formation of same or analogous collection of illustrative plates belongs to the protection domain of the application.Those skilled in the art can compare listed by the application
Collection of illustrative plates and a unknown crystal formation collection of illustrative plates, confirm this two groups of collection of illustrative plates reflection is identical or different crystal formation.
The crystal formation of medicine can generally be obtained by including but is not limited to following method：Melting recrystallization, melting are cold
But, solvent recrystallization, desolventizing, quick volatilization, at a slow speed fast cooling, cooling, steam diffusion and distillation.Crystal formation can pass through X-
Ray powder diffraction (XRPD), differential scanning calorimetric analysis (DSC), thermogravimetric analysis (TGA), single crystal X-ray diffraction, vibrational spectrum
, solid state NMR, infrared spectrum, Raman spectrum, dissolution rate measure, solubility, hygroscopicity etc. are detected, find and sorted out.
Instrument used in the application detection XPRD spectrograms is Bruker D8Advance diffractometers
(diffractometer), θ -2 θ angular instruments, Mo monochromators and Lynxeye detectors, the diffractometer is in copper target wavelength
Operated under conditions of 1.54nm Ka X-rays, 40kV and 40mA.Instrument was detected using preceding with diamond dust.Acquisition software
It is Diffrac Plus XRD Commander, analysis software is MDI Jade5.0.Sample is tested at ambient temperature, need
The sample to be detected is placed on lucite slide.Detailed testing conditions are as follows, angular range：3-40 ° of 2 θ (alterable), step
It is long：0.02 ° of 2 θ, speed：0.2s/ is walked.Unless stated otherwise, sample is not ground before detection.
Differential thermal analysis data are picked up from TA Instruments Q200MDSC, and instrument control software is Thermal
Advantage, analysis software is Universal Analysis.Generally take 1-10 milligrams of sample be positioned over it is uncapped (unless
Special instruction) aluminium crucible in, with 10 DEG C/min programming rate in the case where 50mL/min dries N2 protection by sample from room temperature
250 DEG C are risen to, while thermal change of the TA software records samples in temperature-rise period.Herein, fusing point is by initial temperature
Come what is reported.
Thermogravimetric analysis data is picked up from TA Instruments Q500TGA, and instrument control software is Thermal
Advantage, analysis software is Universal Analysis.Generally take 5-15mg sample to be positioned in platinum crucible, adopt
With the mode of segmentation high resolution detection, with 10 DEG C/min programming rate in the case where 50mL/min dries N2 protection by sample from room
Temperature rise is to 300 DEG C, while weight change of the TA software records samples in temperature-rise period.
Dynamic moisture content adsorption analysis data are picked up from TA Instruments Q5000TGA, and instrument control software is
Thermal Advantage, analysis software is Universal Analysis.1-10mg sample is generally taken to be positioned over platinum earthenware
In crucible, TA software records sample is in relative humidity from 0% to 90% again to the weight change in 0% change procedure.According to the tool of sample
Body situation, also can use different absorption and De contamination step to sample.
In some embodiments, the experiment that the application is related to is operated in room temperature or close under conditions of room temperature, either
Carried out under conditions of identical with the temperature in room or fume hood or close.Usual experimental temperature is 15 DEG C to 25 DEG C, preferably
17 DEG C to 22 DEG C.
In some embodiments, the experimental method or step that the application is related to can be operated in the case of " staying overnight ".
So-called " staying overnight " refers to the time that experimental procedure crosses over evening, without positive ground observation experiment phenomenon during overnight." mistake
The time of experiment at night " can be from 8 to 22 hours, preferably 10-18 hours, more preferably 16 hours.
Unless stated otherwise, the crystal formation described in this application can pass through drying steps.Drying can in room temperature or more
High temperature is carried out.Crystal-form substances can be dried at a temperature of about 20 DEG C to about 60 DEG C, preferably 20 DEG C to 50 DEG C, more preferably 20
DEG C to 40 DEG C.Dry time span can be from 2 hours to 48 hours, or stay overnight.Drying can be in fume hood, convection oven
Or carried out in vacuum drying oven.
Unless stated otherwise, so-called " anhydrous " refers to that triazole [4,5-d] pyrimidine compound crystal formation contains through TGA measurements herein
There are not more than 1.5% (weight ratio), the water or organic solvent of preferably no more than 1% (weight ratio).
The crystallization mode used in this application includes：Room temperature volatilization, slow volatilization, magma precipitation, chelating polymer template are waved
Hair, cooling recrystallization and anti-solvent recrystallization.
Room temperature volatilization is placed on sample settled solution in the 5mL vials of opening, under specific temperature conditions (generally
For room temperature) volatilization.Nitrogen can be used to purge or directly volatilize at room temperature.
Slow volatilization is that sample settled solution is placed in the 5mL vials of punching, is placed in air and slowly volatilizees.
Purged during this without using nitrogen.
It is to stir the supersaturated solution (with the presence of undissolved solid) of sample in different solvents system that magma, which is separated out, is led to
Normal 2 hours to 2 time-of-weeks.Suck after supernatant, take solid matter to do XRD detections.
Chelating polymer template volatilization is consistent with room temperature evaporation method, but with the addition of a small amount of not soluble high molecular in sample solution
In.Wherein so-called " a small amount of " refers to 5% that high molecular content is no more than triazole [4,5-d] pyrimidine compound weight, preferably more than
4%, more preferably less than 3%.
It is to be dissolved a sample under specific hot conditions in appropriate solvent to cool down recrystallization, is placed on 5mL vials
In, alternating temperature shaking table is placed in, cools successively according to certain rate of temperature fall, is stirred overnight at room temperature.The temperature of experiment can be from 75 DEG C to 0
DEG C, preferably 50 DEG C to 15 DEG C.In each specific temperature, sample solution is incubated 1 hour to 2 days.Suck and taken after supernatant admittedly
XRD is surveyed in physical examination.Sometimes, solid matter can pass through drying steps.
Anti-solvent recrystallization is to take sample to be dissolved in good solvent, and ultrasound dissolves it, adds appropriate anti-solvent, and room temperature is stirred
Mix.
In some embodiments, using polymeric stencil evaporation method, crystal formation is helped to crystallize using macromolecule, wherein
Macromolecule used is selected from：Polyacrylic acid (PAA), PDDA (PDADMAC) and polyallyl amine salt
Hydrochlorate (PAHPAH).
In this application, PAA used is the solid that molecular weight is 1800.There is unbodied XRD to show for it, and
There is no fusing point in DSC.PAA X-ray powder diffraction figure is in Figure 19.PAA DSC and TGA figures are in Figure 20.
In this application, PAH used is solid of the molecular weight 15000 or so.There is unbodied XRD to show for it,
And there is no fusing point in DSC.PAH X-ray powder diffraction figure is in Figure 21.PAH DSC and TGA figures are in Figure 22.
In this application, the PDADMAC used is the aqueous suspension that content is 35% (weight ratio).Its molecular weight is few
In 100000.There is unbodied XRD to show for it, and without performance fusing point in DSC.PDADMAC X-ray powder diffraction
Figure is in Figure 23.PDADMAC DSC and TGA figures are in Figure 24.
Polymer substance used in this application is amorphous, and DSC does not show fusing point.Due to high molecular
Usage amount is strictly controlled at less than 5%, it is believed that the macromolecule used in experiment does not interfere with the judgement of crystal formation, Hou Zhetong
Often judged by X-ray diffractogram and DSC etc..
In this application, used initial substance triazole [4,5-d] pyrimidine compound can be special according to WO2001092262A
Method described in profit application prepares crystal formation I, II and III of triazole [4,5-d] pyrimidine compound, its XRD spectrum and patent
The collection of illustrative plates of offer is consistent.The initial substance generally used in this application is crystal formation I, III and the nothing described by the patent application
Amorphous mass.
The novel crystal forms of triazole [4,5-d] pyrimidine compound described herein, which compare known crystal formation, to be had in advantages below
It is one or more：Higher crystallinity, solubility, dissolution rate, particle shape, thermodynamics and mechanical stability, low moisture absorption
Property, more preferable mobility, compressibility and apparent density.
Pass through the detailed description carried out above by reference to accompanying drawing to the application, other purposes, feature, advantage and the side of the application
Face will be apparent to those skilled in the art.Therefore, above is referred to the embodiment of the application be only to show
Example property, those skilled in the art can make after present specification has been read in spirit herein and category to it
Various obvious changes and modification, these changes and modification are also covered by within the protection domain of appended claims.
Embodiment
It will be helpful to further understand the application by following embodiments, but these embodiments bel not applied to limit this Shen
Content please.
Starting triazole [4,5-d] pyrimidine compound that the application is used is by being commercially available.Crystal formation I, II of the compound and
III preparation method is identical with the description in document CN1432018A (WO2001/0922621A).
Embodiment 1：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 1 and crystal formation 2
Taken under normal temperature in 30mg triazoles [4,5-d] pyrimidine compound crystal formation III, the loosely capped vial for being added to 5 milliliters, thereto
Add 1.5mL methanol, system whole dissolved clarification.1.37mg PDDA solid is added in the solution,
Suspension is obtained, system is warming up to 50 DEG C, stirred 1 hour by ultrasound 1 minute.PDDA is in solid
Graininess is scattered in the solution.Reaction solution removal thermal source is cooled to after room temperature and volatilized in fume hood.Take the solid wet of precipitation
Sample detection XRPD turns out to be triazole [4,5-d] pyrimidine compound crystal formation 1.After solvent volatilization completely is dry, the solid of precipitation is taken to do
Sample detection XRPD turns out to be triazole [4,5-d] pyrimidine compound crystal formation 2.
Embodiment 2：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 2
10mg triazole [4,5-d] pyrimidine compound crystal formation III is taken, is placed in 5mL vial, the four of 1mL are added
Hydrogen furans, ultrasound 1 minute, solution becomes clarification.Reaction solution is volatilized in room temperature.Solid is taken to detect XRPD cards after solvent volatilization is dry
Real gained material is crystal formation 2.
Embodiment 3：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 2
Taken under normal temperature in 30mg triazoles [4,5-d] pyrimidine compound crystal formation III, the loosely capped vial for being added to 5 milliliters, thereto
Add 1.5mL ethanol, system whole dissolved clarification.1.08mg PDDA is added in the solution, is obtained
System is warming up to 50 DEG C by suspension, ultrasound 1 minute, is stirred 1 hour.PDDA is in solid particle
Shape is scattered in the solution.Reaction solution removal thermal source is cooled to after room temperature and volatilized in fume hood.After solvent volatilization completely is dry,
The solid dry sample of precipitation is taken to detect that XRPD turns out to be triazole [4,5-d] pyrimidine compound crystal formation 2.
Embodiment 4：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 3
3mg triazole [4,5-d] pyrimidine compound crystal formation I is taken, is placed in 5mL vial, 1mL bis- Evil are added
Alkane, solution clarification, ultrasound 1 minute.Place reaction liquid into fume hood in room temperature volatilization.The detection XRPD cards after solvent volatilization is dry
Real gained material is crystal formation 3.
Embodiment 5：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 8 and crystal formation 4
3mg triazole [4,5-d] pyrimidine compound crystal formation III is taken, is placed in 5mL vial, positive the third of 1mL is added
Alcohol, ultrasound 1 minute takes filtrate to be placed in the bottle of punching in room temperature volatilization after filtering.Solid wet sample is taken to detect that XRPD confirms institute
It is crystal formation 8 to obtain material.Detection XRPD after dry solvent that sample is volatilized completely in atmosphere confirms that sample has switched to crystal formation 4.
Embodiment 6：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 4
10mg triazole [4,5-d] pyrimidine compound crystal formation III is taken, is placed in 5mL vial, adds 0.1mL's
The isopropyl ether of methanol and 1mL, covers tightly bottle cap.System temperature is risen into 55 DEG C, ultrasound 1 minute, solution clarification.By reaction solution 55
DEG C stirring 1 hour, is down to 50 DEG C by system temperature by 5 DEG C/h of speed, stirs 1 hour.Then same speed is pressed by body
Be that temperature is down to 45 DEG C, 37 DEG C, 35 DEG C and room temperature, each temperature and stir 1 hour.It is stirred at room temperature overnight.Separate out
Solid wet sample by XRPD detection turn out to be crystal formation 4.Open bottle cap to continue to volatilize in the fume hood of room temperature, treat that solvent is complete
The detection of solid dry sample is taken to confirm that sample is still crystal formation 4 after volatilization is dry.
Embodiment 7：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 5 and crystal formation 4
10mg triazole [4,5-d] pyrimidine compound crystal formation III is taken, is placed in 5mL vial, adds 0.65mL's
The water of ethanol and 1mL, covers tightly bottle cap.System temperature is risen into 55 DEG C, ultrasound 1 minute, solution clarification.Reaction solution is stirred at 55 DEG C
Mix 1 hour, system temperature is down to 50 DEG C by 5 DEG C/h of speed, stirred 1 hour.Then same speed is pressed by system temperature
Degree be down to 45 DEG C, 37 DEG C, 35 DEG C and room temperature, each temperature and stir 1 hour.It is stirred at room temperature overnight.What is separated out consolidates
The wet sample of body turns out to be crystal formation 5 by XRPD detections.Open bottle cap to continue to volatilize in the fume hood of room temperature, treat that solvent volatilizees completely
The detection of solid dry sample is taken to confirm that sample switchs to crystal formation 4 after dry.
Embodiment 8：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 6 and crystal formation 4
10mg triazole [4,5-d] pyrimidine compound crystal formation III is taken, is placed in 5mL vial, adds 0.25mL's
The water of acetone and 1mL, covers tightly bottle cap.System temperature is risen into 55 DEG C, ultrasound 1 minute, solution clarification.Reaction solution is stirred at 55 DEG C
Mix 1 hour, system temperature is down to 50 DEG C by 5 DEG C/h of speed, stirred 1 hour.Then same speed is pressed by system temperature
Degree be down to 45 DEG C, 37 DEG C, 35 DEG C and room temperature, each temperature and stir 1 hour.It is stirred at room temperature overnight.What is separated out consolidates
The wet sample of body turns out to be crystal formation 6 by XRPD detections.Open bottle cap to continue to volatilize in the fume hood of room temperature, treat that solvent is volatilized completely
After take solid dry sample detection confirm sample switch to crystal formation 4.
Embodiment 9：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 7 and crystal formation 4
10mg triazole [4,5-d] pyrimidine compound crystal formation III is taken, is placed in 5mL vial, adds 0.65mL's
The water of ethanol and 1mL, covers tightly bottle cap.System temperature is risen into 55 DEG C, ultrasound 1 minute, solution clarification.Reaction solution is stirred at 55 DEG C
Mix 1 hour, system temperature is down to 50 DEG C by 5 DEG C/h of speed, stirred 1 hour.Then same speed is pressed by system temperature
Degree be down to 45 DEG C, 37 DEG C, 35 DEG C and room temperature, each temperature and stir 1 hour.It is stirred at room temperature overnight.What is separated out consolidates
The wet sample of body turns out to be crystal formation 7 by XRPD detections.Open bottle cap to continue to volatilize in the fume hood of room temperature, treat that solvent is volatilized completely
After take solid dry sample detection confirm sample switch to crystal formation 4.
Embodiment 10：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 7
10mg triazole [4,5-d] pyrimidine compound crystal formation III is taken, is placed in 5mL vial, adds 0.1mL's
Ethanol, ultrasound 1 minute, system dissolved clarification.2mL water is added with the speed of 0.1mL/ minutes, reaction solution starts to separate out solid.Will be anti-
Liquid is answered to be stirred at room temperature overnight, the solid wet sample of precipitation turns out to be crystal formation 7 by XRPD detections.
Embodiment 11：The preparation of triazole [4,5-d] pyrimidine compound crystal formation 9
6mg triazole [4,5-d] pyrimidine compound crystal formation 4 and 6mg triazole [4,5-d] pyrimidine compound crystal formation I are taken, is put
In in 5mL vial, 0.6mL water is added, paste liquid is obtained, this pulpous state liquid is stirred at room temperature three days, solid mistake
After filter, 40 DEG C of dryings 2 hours are detected as crystal formation 9 by XRPD.
Claims (7)
- The crystal formation 2 of formula 1. (I) compound,It is characterized in 5.2 °, 9.6 °, 10.7 °, 14.9 °, 17.5 ° and 19.4 ° ± 0.2 ° of 2 θ through X-ray powder diffraction has feature Peak.
- 2. the crystal formation 2 of formula (I) compound according to claim 1, wherein the crystal formation 2 is further at 5.2 °, 9.6 °, 10.7 °, 14.9 °, 15.7 °, 17.5 °, 19.4 °, 20.7 °, 21.2 °, 21.5 °, 22.4 °, and 25.6 ° of ± 0.2 ° of 2 θ have feature Peak.
- 3. the crystal formation 2 of formula (I) compound according to claim 1 or 2, wherein the crystal formation 2 is further in differential thermal analysis Melting start temperature on scanning curve is in the range of 149-153 DEG C.
- 4. the preparation method of the crystal formation 2 of formula (I) compound any one of claim 1-3, the preparation method includes By the dissolving of raw material formula (I) compound in organic solvent, then volatilized by room temperature, room temperature magma is separated out or polymeric stencil Evaporation method makes to obtain anhydride after solvent volatilization is dry；WhereinThe solvent Wei dioxanes, tetrahydrofuran, methanol, ethanol or normal propyl alcohol.
- 5. a kind of pharmaceutical composition, includes the crystalline substance of formula (I) compound any one of the claim 1-3 of therapeutically effective amount Type 2 and pharmaceutically acceptable excipient.
- 6. the crystal formation 2 of formula (I) compound any one of claim 1-3 is being prepared for treating or preventing with coronal Purposes in the medicine of the Arterial thrombosis complication of the patient of artery, the cerebrovascular or peripheral artery disease.
- 7. the crystal formation 2 of formula (I) compound any one of claim 1-3 is preparing growth and expansion for pre- preventing tumor Purposes in scattered medicine.
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| CN1432018A (en) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | Crystalline and amorphous form of triazolo (4,5-d) pyrimidine compound |
| CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
| WO2012063126A2 (en) * | 2010-11-09 | 2012-05-18 | Actavis Group Ptc Ehf | Improved processes for preparing pure (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahdro-3ah-cyclopenta[d] [1,3]-dioxol-4-ol and its key starting material |
| CN102675321A (en) * | 2012-05-11 | 2012-09-19 | 上海皓元化学科技有限公司 | Preparation method of ticagrelor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1432018A (en) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | Crystalline and amorphous form of triazolo (4,5-d) pyrimidine compound |
| CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
| WO2012063126A2 (en) * | 2010-11-09 | 2012-05-18 | Actavis Group Ptc Ehf | Improved processes for preparing pure (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahdro-3ah-cyclopenta[d] [1,3]-dioxol-4-ol and its key starting material |
| CN102675321A (en) * | 2012-05-11 | 2012-09-19 | 上海皓元化学科技有限公司 | Preparation method of ticagrelor |
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| CN106496234A (en) | 2017-03-15 |
| CN104211704A (en) | 2014-12-17 |
| CN106496235A (en) | 2017-03-15 |
| CN106496234B (en) | 2019-08-30 |
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