CN106905294A - Crystal formation of 5 [2,6 2 (4 morpholinyl) 4 pyrimidine radicals] 4 (trifluoromethyl) 2 pyridine amine and preparation method thereof - Google Patents
Crystal formation of 5 [2,6 2 (4 morpholinyl) 4 pyrimidine radicals] 4 (trifluoromethyl) 2 pyridine amine and preparation method thereof Download PDFInfo
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- CN106905294A CN106905294A CN201610536514.8A CN201610536514A CN106905294A CN 106905294 A CN106905294 A CN 106905294A CN 201610536514 A CN201610536514 A CN 201610536514A CN 106905294 A CN106905294 A CN 106905294A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
Crystal formation the present invention relates to 5 [2,6 two (4 morpholinyl) 4 pyrimidine radicals] 4 (trifluoromethyl) 2 pyridine amine and preparation method thereof, in particular crystal formation A and crystal formation C.The stability of crystal form that the present invention is provided is well, solubility is higher, it is moist relatively low to draw, and has important value to the optimization and exploitation of the following medicine.
Description
Technical field
The present invention relates to chemical medicine, more particularly to 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (three
Methyl fluoride) -2- pyridine amine crystal formation and preparation method thereof.
Background technology
5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridines amine (compound of formula I), also known as
BKM120 (Buparlisib), is the breast cancer new drug researched and developed by Novartis (Novartis) company.Current medicine treatment metastatic
Breast cancer research is in III phases clinical and confirmatory I/II phases clinical stage.BKM120 is I class PI-3 kinases
(PIK3) reversible inhibitor, result of study shows that it has antitumor activity to ER positive breast cancer cell lines and plantation knurl, can
Simple application or combined endocrine therapy.
Polymorphism is widely present in medicine.The different crystal forms of same medicine are in solubility, fusing point, density, stabilization
Property etc. aspect have significant difference so as to some extent the influence stability of medicine, homogeneity, bioavilability, curative effect and
Security.Therefore, comprehensive and systematic screening polymorph is carried out in medicament research and development, selection is best suitable for the crystal formation of exploitation, is to neglect
Depending on one of important research content.
The free form and hydrochloride of compound of formula I are described in patent CN101389622A, with and the public affairs of embodiment 10
Open for preparing the method for compound of formula I and the pale solid of compound of formula I.Wherein described preparation method is although suitable
Close, but be not considered conducive to commercially produce.
Patent CN103140479A discloses the crystal form of compound of formula I and its crystal form of salt.Specifically, patent
Two crystal formations of free form of compound of formula I are disclosed, respectively semihydrate Ha and anhydrous form A also discloses Formulas I
Several crystal formations of compound mono-hydrochloric salts, respectively monohydrate Ha, anhydride form A, form B and solvate form thereof Sa, shape
Formula Sb, form Sc, form Sd and form Se.And compared with salt, free form can generally shorten processing procedure, reduces cost.
The invention provides two kinds of novel crystal forms of compound of formula I free form, dissolved than anhydrous form A of the prior art
Du Genggao, the novel crystal forms preparation process is simple that the present invention is provided, and good stability, low in hygroscopicity, meet medicinal requirements, are medicine
Exploitation provide preferably selection.
The content of the invention
Applicant is carrying out the polycrystalline of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine
In type screening, two kinds of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine are found surprisingly that
Novel crystal forms, are respectively designated as crystal formation A and crystal formation C.Novel crystal forms in the present invention have good stability, low in hygroscopicity, patent
Compared to having solubility higher, for improving drug effect, reduce medicine carrying capacity has anhydrous form A disclosed in CN103140479 A
Important meaning.There is important value to the optimization and exploitation of the following medicine.
A specific aspect of the invention, a kind of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] of present invention offer -
The crystal formation A of 4- (trifluoromethyl) -2- pyridine amine, X-ray powder diffraction figures of the crystal formation A at 25 DEG C is 9.8 ° in 2theta values
± 0.2 °, 15.7 ° ± 0.2 °, there is at 8.0 ° ± 0.2 ° characteristic peak.
Further, the present invention provide crystal formation A X-ray powder diffraction figure also 2theta values for 12.1 ° ±
0.2 °, 16.7 ° ± 0.2 °, in 18.0 ° ± 0.2 ° one or at two or at three there is characteristic peak；Preferably, the present invention is provided
Crystal formation A X-ray powder diffraction figure 2theta values be 12.1 ° ± 0.2 °, 16.7 ° ± 0.2 °, locate tool in 18.0 ° ± 0.2 °
There is characteristic peak.
Further, the present invention provide crystal formation A X-ray powder diffraction figure also 2theta values for 20.7 ° ±
0.2 °, 15.1 ° ± 0.2 °, in 18.5 ° ± 0.2 ° one or at two or at three there is characteristic peak；Preferably, the present invention is provided
Crystal formation A X-ray powder diffraction figure 2theta values be 20.7 ° ± 0.2 °, 15.1 ° ± 0.2 °, locate tool in 18.5 ° ± 0.2 °
There is characteristic peak
One of the invention specific and preferred aspect, the X-ray powder diffraction figure of crystal formation A is also in 2theta values
9.8°±0.2°、15.7°±0.2°、8.0°±0.2°、12.1°±0.2°、16.7°±0.2°、18.0°±0.2°、20.7°±
0.2 °, 15.1 ° ± 0.2 °, be respectively provided with characteristic peak at 18.5 ° ± 0.2 °.In a specific embodiment according to the program,
The X-ray powder diffraction figure of crystal formation A is substantially as shown in Figure 1.
Preferably, the crystal formation A that the present invention is provided, is being heated to starting endothermic peak occur near 155 DEG C, its differential scanning amount
Thermal analysis curue is substantially as shown in Figure 2.
Preferably, the crystal formation A that the present invention is provided, when being heated to 150 DEG C, with about 0.2% weight loss gradient, its
Thermogravimetric analysis figure is substantially as shown in Figure 3.
It is a further object to provide a kind of preparation method of crystal formation A, the crystal formation A makes by the following method
：
The solid of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine is added to alcohol
In class, halogenated hydrocarbon, the single or mixed solvent of ether solvent, volatilization is i.e. available.
Further, the solvent is the mixed solvent of dichloromethane and methyl alcohol.
Another specific aspect of the invention, the present invention provides a kind of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidines
Base] -4- (trifluoromethyl) -2- pyridine amine crystal formation C, X-ray powder diffraction figures of the crystal formation C at 25 DEG C be in 2theta values
16.1 ° ± 0.2 °, 7.3 ° ± 0.2 °, there is at 6.9 ° ± 0.2 ° characteristic peak.
Further, the present invention provide crystal formation C X-ray powder diffraction figure also 2theta values for 14.0 ° ±
0.2 °, in 10.2 ° ± 0.2 ° one or at two there is characteristic peak；Preferably, the x-ray powder of the crystal formation C that the present invention is provided
Diffraction pattern 2theta values be 14.0 ° ± 0.2 °, place has characteristic peak in 10.2 ° ± 0.2 °.
Further, the present invention provide crystal formation C X-ray powder diffraction figure also 2theta values for 19.6 ° ±
0.2 °, in 17.3 ° ± 0.2 ° one or at two there is characteristic peak；Preferably, the x-ray powder of the crystal formation C that the present invention is provided
Diffraction pattern 2theta values be 19.6 ° ± 0.2 °, place has characteristic peak in 17.3 ° ± 0.2 °
One of the invention specific and preferred aspect, the X-ray powder diffraction figure of crystal formation C is also in 2theta values
16.1°±0.2°、7.3°±0.2°、6.9°±0.2°、14.0°±0.2°、10.2°±0.2°、19.6°±0.2°、17.3°±
Characteristic peak is respectively provided with 0.2 °.In a specific embodiment according to the program, the X-ray powder diffraction figure base of crystal formation C
This is as shown in Figure 4.
Preferably, the crystal formation C that the present invention is provided, is being heated to starting first endothermic peak occur near 73.4 DEG C, is adding
Heat nearby starts second endothermic peak occur to 143.9 DEG C, and its differential scanning calorimetric thermogram is substantially as shown in Figure 5.
Preferably, the crystal formation C that the present invention is provided, when being heated to 150 DEG C, with about 7.6% weight loss gradient, its
Thermogravimetric analysis figure is substantially as shown in Figure 6.
It is a further object to provide a kind of preparation method of crystal formation C, the crystal formation C makes by the following method
：
The solid of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine is added to one kind
Or in the mixed system of various alcohols solvents, then to be placed in diffusion under anti-solvent atmosphere i.e. available.
Further, the anti-solvent is water.
Formula (I) compound in the present invention can be solid, semisolid, wax or the oil form of formula (I) compound.
It is a further object to provide a kind of Pharmaceutical composition, 5- of the Pharmaceutical composition comprising effective dose
[2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridines amine and pharmaceutically acceptable auxiliary material.That is, it is medicinal
Active component in composition can be 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (fluoroforms of any crystal form
Base) one or more in -2- pyridine amine of mixing can be crystal formation A, crystal formation C or both mixtures specifically.
In the present invention, " crystal " or " crystal formation " refers to characterizing what is confirmed by shown X-ray diffractogram.This area skill
Art personnel it is understood that physicochemical property discussed herein can be characterized, experimental error therein depend on instrument condition,
The preparation of sample and the purity of sample.Particularly, as well known to those skilled in the art, X-ray diffractogram would generally be with instrument
Condition and change.In particular, the relative intensity of X-ray diffractogram is likely to the change of experiment condition
And change, so the order of peak intensity cannot function as unique or deciding factor.In addition, the experimental error of peak angle degree generally exists
5% or less, the error of these angles should also be considered into, allow generally for ± 0.2 ° of error.Further, since sample
The influence of the empirical factors such as height, can cause the overall offset of peak angle degree, allow generally for certain skew.Thus, this area skill
Art personnel are it is understood that an x-ray diffraction pattern for crystal formation need not be penetrated with the X in example referred herein in the present invention
Ray diffraction diagram is completely the same.It is any with belonging to the present invention with the crystal formation of the same or analogous figure of characteristic peak in these collection of illustrative plates
Category within.Those skilled in the art can compare the collection of illustrative plates of the collection of illustrative plates listed by the present invention and a unknown crystal formation, with
Confirm this two groups of collection of illustrative plates reflections is identical or different crystal formation.
" crystal formation " and " polymorphic " and other relative words refer to solid chemical compound in crystal structure in the present invention
In with specific crystal form state exist.The difference of polymorphic physicochemical property can be embodied in storage stability, compressibility, close
The aspects such as degree, dissolution rate.In extreme situations, the difference of solubility or dissolution rate can cause medicine poorly efficient, or even
Toxicity.
Term " treatment " used in the present invention refers to one of the following or various：(1) prevention disease；For example can
Disease, illness or obstacle can be tended to, prevented in the individuality of the lesion of the disease or symptom but without being subjected to or show
The disease, illness or obstacle；(2) disease is suppressed；For example just it is being subjected to or is showing the lesion of the disease, illness or obstacle or disease
Suppress the disease, illness or obstacle in the individuality of shape；And (3) improve the disease；For example, being subjected to or showing the disease, disease
Improve the disease, illness or obstacle (reversing lesion and/or symptom) in the individuality of the lesion or symptom of disease or obstacle, for example, subtract
The severity of low disease.
In some embodiments, novel crystal forms of the invention, including crystal formation A or crystal formation C are pure, single, are not had substantially
Have and mix any other crystal formation.In the present invention, " not having substantially " refers to that this crystal formation contains less than 20% when novel crystal forms are used to refer to
Other crystal formations of (weight), especially less than other crystal formations of 10% (weight), more refer to other crystal formations less than 5% (weight),
More refer to other crystal formations less than 1% (weight).
It should be noted that the numerical value referred in the present invention and number range should not be narrowly interpreted as numerical value or numerical value
Scope in itself, it should be understood by those skilled in the art that it can be according to the difference of particular technique environment, without departing substantially from essence of the invention
Floated around concrete numerical value on the basis of god and principle, in the present invention, this foreseeable floating of those skilled in the art
Scope is more to be represented with term " about ".
The polymorphic of medicine can be obtained by including but is not limited to following method：Melting recrystallization, melting cooling, solvent
Recrystallize, lose solvent, quick volatilization, at a slow speed fast cooling, cooling, steam diffusion and distillation.Sometimes, different methods is likely to
Obtain identical crystallization.Polymorphic can be by X-ray powder diffraction (XRPD), differential scanning calorimetric analysis (DSC), thermogravimetric point
(TGA), light microscope technique, hygroscopicity etc. is analysed to detect, find and sort out.
Additionally, the present invention provides a kind of Pharmaceutical composition, the Pharmaceutical composition is comprising treatment and/or prevention effective dose
The mixing of crystal formation A of the present invention or crystal formation C or both, and at least one pharmaceutically acceptable excipient.
Above-mentioned Pharmaceutical composition can be made into certain formulation, is administered by the approach being adapted to.Such as oral, parenteral (bag
Include subcutaneous, muscle, vein or intracutaneous), rectum, transdermal, the approach such as intranasal.The formulation for being adapted to be administered orally includes tablet, capsule
Agent, granule, powder, pill, pulvis, lozenge, solution, syrup or supensoid agent, as needed, may be adapted to active constituents of medicine
Quick release, sustained release or regulation release；The formulation for being adapted to parenteral includes aqueous or non-aqueous aseptic injection
Solution, emulsion or suspension；The formulation for being adapted to rectally includes suppository or enema；It is adapted to the formulation of cutaneous penetration including soft
Cream, creme, patch；The formulation for being adapted to nose administration includes aerosol, spray, nasal drop.
Acceptable excipient in above-mentioned Pharmaceutical composition Chinese pharmacology, in the case of solid oral dosage form, including but not
It is limited to：Diluent, such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium monohydrogen phosphate, tricalcium phosphate,
Mannitol, sorbierite, sugar etc.；Adhesive, such as Arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxy propyl cellulose
Element, hydroxypropyl methyl cellulose, polyethylene glycol etc.；Disintegrant, such as starch, sodium starch glycollate, pregelatinized starch, crosslinking
PVP, Ac-Di-Sol, cataloid etc.；Lubricant, such as stearic acid, magnesium stearate, zinc stearate,
Sodium Benzoate, sodium acetate etc.；Glidant, such as cataloid etc.；Complex forming agents, such as cyclodextrin of various ranks
And resin；Rate of release controlling agent, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose
Element, methylcellulose, methyl methacrylate, wax etc..Available other pharmaceutically acceptable excipient are included but is not limited to
Film forming agent, plasticizer, colouring agent, flavor enhancement, viscosity modifier, preservative, antioxidant etc..Optionally, tablet is coated and is wrapped
Clothing layer, for example, provide shellac isolation coat, sugar-coat or polymer coating, the polymer such as hydroxypropyl methyl fiber in coatings
Element, polyvinyl alcohol, ethyl cellulose, methacrylic polymer, hydroxypropyl cellulose or starch, can also include antisticking
Agent such as silica, talcum powder, opacifiers such as titanium dioxide, colouring agent such as iron oxides colouring agent.In liquid oral dosage form
In the case of, suitable excipient is including water, oils, alcohols, glycols, flavor enhancement, preservative, stabilizer, colouring agent etc.；Water or
Non-aqueous sterile suspensions can contain suspending agent and thickener；Excipient suitable for aqueous suspension includes rubber polymer or natural
Glue such as gum arabic, Siberian cocklebur natural gum, alginates, glucan, sodium carboxymethylcellulose, methylcellulose, polyvinyl pyrrole
Alkanone or gelatin.In the case of parenteral dosage forms, the excipient of water or non-aqueous aseptic injectable solution is usually aseptic
Water, physiological saline or D/W, containing buffer, antioxidant, bacteriostatic agent and can make the Pharmaceutical composition
The solute isotonic with blood.Each excipient must be it is acceptable, can it is compatible with the other compositions in formula and for
Patient is harmless.
The Pharmaceutical composition can be using preparing well known to a person skilled in the art method in the prior art.Prepare medicine
When using composition, by the mixing of crystal formation A of the present invention, crystal formation C or both and one or more pharmaceutically acceptable excipient phase
Mixing, optionally mixes with one or more other active constituents of medicine.For example, tablet, capsule, granule can lead to
The techniques such as mixing, granulation, compressing tablet or filling capsule are crossed to prepare；Pulvis is by by the finely ground active constituents of medicine to suitable size
And excipient mixes to prepare；Solution and syrup can be dissolved in suitably seasoned water or aqueous molten by by active constituents of medicine
Prepared in liquid；Supensoid agent can be prepared by the way that active constituents of medicine is scattered in pharmaceutically acceptable carrier.
It is especially mentioned that the wet granulation technology of solid pharmaceutical preparation, by taking the wet granulation of tablet as an example, preparation technology is：It is mixed
The dry solids such as active component, filler, adhesive are closed, is soaked with wetting agent such as water or alcohol, the solid of the wetting is made solidifying
Polymers or granule, continue wet granulation, until the uniform grading required by acquisition, are subsequently dried the granular product.Then will
The dry particle for obtaining and disintegrant, lubricant, antitack agent etc. mix, the compressing tablet in pelleter；Alternatively, with appropriate bag
Clothing powder is coated.
Additionally, also it is especially mentioned that oral suspensions, an advantage of this form of medication is that patient may not necessarily gulp down
Pharynx solid form, particularly with swallowing the elderly, children or oral cavity, the patient of injury of throat that solid form may have any problem.
Supensoid agent is the binary system for forming solid particle dispersions in a liquid, and it is still kept in the water or aqueous carrier of supensoid agent
The crystal of original solid form is expected the stabilization that would be even more beneficial to keep drug products property.Other groups in oral suspensions
Dividing may include buffer, surfactant, viscosity modifier, preservative, antioxidant, colouring agent, flavor enhancement, taste masking agent
Deng.
Crystal formation A of the present invention and crystal formation C that the present invention is provided have the favorable property suitable for above-mentioned formulation.
In the present invention, usually by 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (fluoroforms of therapeutically effective amount
Base) mixing of -2- pyridines amine crystal formation A or crystal formation C or both mixes or contacts and be made medicinal group with one or more pharmaceutic adjuvant
Compound or preparation, the Pharmaceutical composition or preparation are prepared in well known mode in pharmaceutical field.
Further, Pharmaceutical composition of the present invention can be used for treating cancer, particularly metastatic breast cancer.
It is a further object to provide a kind of 5- of crystal form [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -
The use being mixed in preparation treating cancer pharmaceutical preparation of the crystal formation A or crystal formation C of 4- (trifluoromethyl) -2- pyridine amine or both
On the way, the purposes of the pharmaceutical preparation for the treatment of metastatic breast cancer is particularly prepared.
It is a further object to provide a kind of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (fluoroforms
Base) -2- pyridine amine crystal formation A or crystal formation C or both the purposes being blended in treating cancer, particularly treat metastatic mammary gland
The purposes of cancer.
Beneficial effects of the present invention are：
The crystal formation A and crystal formation C that the present invention is provided have good stability, can well avoid medicine from storing and develop
During occur turn crystalline substance, so as to avoid the change of bioavilability and drug effect.The crystal formation ratio that the present invention is provided is in the prior art
Anhydrous form A solubility it is higher, for improve drug effect, reduce medicine carrying capacity be significant.The crystal formation that the present invention is provided draws
It is moist relatively low, it is difficult to be influenceed and deliquescence by high humility, facilitate the long-term storage of medicine to place.The crystal morphology that the present invention is provided is complete
Whole, crystallinity is high, and granularity is moderate, beneficial to the filtration drying in follow-up commercial process.It is prepared by the crystal formation that the present invention is provided
It is simple to operate, it is with low cost, there is important value to the optimization and exploitation of the following medicine.
Brief description of the drawings
Fig. 1 schemes for the XRPD of crystal formation A；
Fig. 2 schemes for the DSC of crystal formation A；
Fig. 3 schemes for the TGA of crystal formation A；
Fig. 4 is the XRPD of crystal formation C；
Fig. 5 schemes for the DSC of crystal formation C；
Fig. 6 schemes for the TGA of crystal formation C；
Fig. 7 is crystal formation A's1H NMR scheme；
Fig. 8 is crystal formation C's1H NMR scheme；
Fig. 9 schemes for the DVS of crystal formation A；
For the XRPD figures before and after the DVS of crystal formation A, (upper figure is the XRPD figures before DVS to Figure 10, and figure below is the XRPD after DVS
Figure)；
Figure 11 schemes for the DVS of crystal formation C；
For the XRPD figures before and after the DVS of crystal formation C, (upper figure is the XRPD figures before DVS to Figure 12, and figure below is the XRPD after DVS
Figure)；
Figure 13 is that crystal formation A places the stability XRPD comparison diagrams of 30 days under 25 DEG C/60% relative humidities (upper figure is put
XRPD figures before putting, figure below is the XRPD figures after placing)；
Figure 14 is that crystal formation A places the stability XRPD comparison diagrams of 30 days under 40 DEG C/75% relative humidities (upper figure is put
XRPD figures before putting, figure below is the XRPD figures after placing)；
Figure 15 is that crystal formation A places the stability XRPD comparison diagrams of 30 days under 60 DEG C/75% relative humidities (upper figure is put
XRPD figures before putting, figure below is the XRPD figures after placing)；
Figure 16 is the stability XRPD comparison diagrams of crystal formation A placements 30 days under 80 DEG C of relative humidities (before upper figure is placed
XRPD figure, figure below be place after XRPD figure)；
Figure 17 is that crystal formation C places the stability XRPD comparison diagrams of 30 days under 25 DEG C/60% relative humidities (upper figure is put
XRPD figures before putting, figure below is the XRPD figures after placing)；
Figure 18 is that crystal formation C places the stability XRPD comparison diagrams of 30 days under 40 DEG C/75% relative humidities (upper figure is put
XRPD figures before putting, figure below is the XRPD figures after placing)；
Specific embodiment
Hereinafter the present invention, but the protection domain being not intended to limit the invention will be expanded on further by specific embodiment.
Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, and these improvement also should be regarded as
Protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
In following embodiments, the condition that described test method is generally advised according to normal condition or manufacturer is implemented；
The initiation material of described 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine is by commercially available
Method is obtained.
Used abbreviation is explained as follows in the present invention：
XRPD：X-ray powder diffraction
DSC：Differential scanning calorimetric analysis
TGA：Thermogravimetric analysis
DVS：Dynamic water is adsorbed
X-ray powder diffraction figure of the present invention is adopted on Panalytical Empyrean x-ray powder diffraction instruments
Collection, collecting temperature is 25 DEG C or so.The method parameter of X-ray powder diffraction of the present invention is as follows：
X ray reflection parameter：Cu,Kα
1.540598；1.544426
The intensities of K α 2/K α 1：0.50
Voltage：45 KVs (kV)
Electric current：40 milliamperes (mA)
Sweep limits：From 3.0 to 40.0 degree
Differential scanning calorimetric analysis (DSC) figure of the present invention is gathered on TA Q2000.Differential of the present invention
The method parameter of scanning thermometric analysis (DSC) is as follows：
Sweep speed：10℃/min
Protective gas：Nitrogen
Thermogravimetric analysis (TGA) figure of the present invention is gathered on TA Q5000.Thermogravimetric analysis (TGA) of the present invention
Method parameter it is as follows：
Sweep speed：10℃/min
Protective gas：Nitrogen
Dynamic water of the present invention adsorbs (DVS) figure by SMS companies (Surface Measurement Systems
Ltd.) gathered on the Intrinsic dynamic water adsorption instruments of production.The method parameter of described dynamic water adsorption instrument is as follows：
Temperature：25℃
Carrier gas, flow velocity：N2, 200 ml/mins
Unit interval mass change：0.002%/minute
RH range：0%RH-95%RH
Embodiment 1
The preparation method of crystal formation A：
The solid of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine of 6.0mg is molten
Solution is quickly volatilized in the mixed solvent of 0.2mL dichloromethane and 0.3mL methyl alcohol under the conditions of being placed in 50 DEG C, collects solid, through inspection
It is crystal formation A to survey gained solid.
The X-ray powder diffraction data of the crystal formation that the present embodiment is obtained are as shown in table 1.Its XRPD figures such as Fig. 1, its DSC figures
Such as Fig. 2, its TGA figure such as Fig. 3, its1H NMR scheme as shown in fig. 7, its1H NMR datas are as follows：
1H-NMR(400MHz,DMSO-d6)δ8.15(s,1H),6.81(s,1H),6.69(s,2H),6.21(s,1H),
3.68-3.54(m,16H)。
Table 1
Embodiment 2
The preparation method of crystal formation A：
The solid of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine of 10.3mg is molten
Solution is quickly volatilized in the mixed solvent of 0.2mL dichloromethane and 0.3mL methyl alcohol under the conditions of being placed in 50 DEG C, collects solid, through inspection
It is crystal formation A to survey gained solid.Its DVS figures are as shown in Figure 9：
The X-ray powder diffraction data of the crystal formation that the present embodiment is obtained are as shown in table 2.
Table 2
Embodiment 3
The preparation method of crystal formation C：
By the solid dissolving of 9.8mg 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine
In 0.5mL absolute ethyl alcohols, the 3mL bottles that will fill the solution are placed in the 20.0mL bottles for filling 5.0mL water, quiet at room temperature
Put to solid and separate out, centrifuging and taking lower floor solid is dried at room temperature, collect solid, after testing, gained solid is crystal formation C.
The X-ray powder diffraction data of the crystal formation that the present embodiment is obtained are as shown in table 3.Its XRPD figures such as Fig. 4, its DSC figures
Such as Fig. 5, its TGA figure such as Fig. 6, its1H NMR figures such as Fig. 8, its1H NMR datas are as follows：
1H-NMR(400MHz,DMSO-d6)δ8.15(s,1H),6.80(s,1H),6.68(s,2H),6.21(s,1H),
3.67-3.55(m,16H)。
Table 3
Embodiment 4
The preparation method of crystal formation C：
The solid of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine of 10.6mg is molten
In 0.5mL absolute ethyl alcohols, the 3mL bottles that will fill the solution are placed in the 20.0mlL bottles for filling 5.0mL water solution, room temperature
Lower standing to solid is separated out, and centrifuging and taking lower floor solid is dried at room temperature, collects solid, and after testing, gained solid is crystal formation C.
The X-ray powder diffraction data of the crystal formation that the present embodiment is obtained are as shown in table 4.Its DVS figures are as shown in figure 11：
Table 4
Embodiment 5
Crystal formation A, crystal formation C draw moist research：
Each about 10mg of crystal formation A of the invention and crystal formation C are taken respectively it is tested using dynamic water absorption (DVS) instrument draw wet
Property.As shown in table 5, the DVS figures of crystal formation A are as shown in figure 9, crystal formation A tests draw moist front and rear XRPD comparison diagrams such as to experimental result
(upper figure is the XRPD figures before test, and figure below is the XRPD figures after test) shown in Figure 10.The DVS figures of crystal formation C are as shown in figure 11, brilliant
Type C test draw it is moist before and after XRPD comparison diagrams as shown in figure 12 (upper figure be test before XRPD scheme, figure below be test after
XRPD schemes).
Table 5
On draw the description of moist feature with draw moist weightening define that (Chinese Pharmacopoeia version annex XIX J medicines in 2010 draw
Moist test direction principle, experiment condition：25 DEG C ± 1 DEG C, 80% relative humidity)：
Deliquescence：Absorb enough moisture and form liquid
It is great to draw moist：Draw wet weightening not less than 15%
Have and draw moist：Draw wet weightening less than 15% but not less than 2%
Slightly draw moist：Draw wet weightening less than 2% but not less than 0.2%
Nothing is moist almost without drawing：Draw wet weightening less than 0.2%
Embodiment 6
The stability study of crystal formation A：
Take four parts of crystal formation A samples of the invention and be respectively placed in 25 DEG C/60% relative humidity, 40 DEG C/75% relative humidity, 60
DEG C/75% relative humidity, place under the conditions of 80 DEG C 30 days, XRPD is surveyed in then sampling.Result is as shown in table 6：
Table 6
Crystal formation A is in 25 DEG C/60% relative humidity, 40 DEG C/75% relative humidity, 60 DEG C/75% relative humidity, 80 DEG C of conditions
Under, place 30 days crystal formations and keep constant.Above-mentioned result of the test shows that crystal formation A has good stability.
Embodiment 7
The stability study of crystal formation C：
Take four parts of crystal formation C samples of the invention and be respectively placed in 25 DEG C/60% relative humidity, 40 DEG C/75% relative humidity bar
Placed under part 30 days, XRPD is surveyed in then sampling.Result is as shown in table 6：
Table 7
Crystal formation A places 30 days crystal formations and keeps not under 25 DEG C/60% relative humidity, 40 DEG C/75% relative humidities
Become.Above-mentioned result of the test shows that crystal formation C has good stability.
Embodiment 8
The solubility comparative study of crystal formation A and patent CN103140479A anhydrous forms A：
By crystal formation A in the present invention and patent CN103140479A anhydrous forms A (hereinafter referred to as patent anhydrous form A) sample point
Yong not pH 1.8SGF (SGF), pH 5.0FeSSIF (simulated intestinal fluid under simulation fed conditions), pH 6.5FaSSIF (moulds
Intend fasted conditions under simulated intestinal fluid) and high purity water be configured to saturated solution, after 24 hours using high performance liquid chromatography measure
The content of sample in saturated solution.Experimental result is as shown in table 8.
Table 8
Result shows, after placing 24 hours in SGF, FeSSIF, FaSSIF and high purity water crystal formation A of the invention with it is special
Sharp CN103140479A anhydrous forms A is compared, and solubility is higher.
Embodiment 9
The solubility comparative study of crystal formation C and patent CN103140479A anhydrous forms A：
By crystal formation C in the present invention and patent CN103140479A anhydrous forms A (hereinafter referred to as patent anhydrous form A) sample point
Yong not pH 1.8SGF (SGF), pH 5.0FeSSIF (simulated intestinal fluid under simulation fed conditions), pH 6.5FaSSIF (moulds
Intend fasted conditions under simulated intestinal fluid) and high purity water be configured to saturated solution, after 24 hours using high performance liquid chromatography measure
The content of sample in saturated solution.Experimental result is as shown in table 9.
Table 9
Result shows, after placing 24 hours in SGF, FeSSIF, FaSSIF and high purity water crystal formation C of the invention with it is special
Sharp CN103140479A anhydrous forms A is compared, and solubility is higher.
It will be understood by those skilled in the art that under the teaching of this specification, some modifications can be made to the present invention
Or change.These modifications and variations should also be as within the scope of the claims in the present invention.
Claims (14)
1. a kind of crystal formation A of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine, its feature exists
In, its X-ray powder diffraction figure 2theta values be 9.8 ° ± 0.2 °, 15.7 ° ± 0.2 °, 8.0 ° ± 0.2 ° place is with feature
Peak.
2. crystal formation A according to claim 1, it is characterised in that its X-ray powder diffraction figure is 12.1 ° in 2theta values
± 0.2 °, 16.7 ° ± 0.2 °, in 18.0 ° ± 0.2 ° one or at two or at three there is characteristic peak.
3. crystal formation A according to claim 2, it is characterised in that its X-ray powder diffraction figure is 12.1 ° in 2theta values
± 0.2 °, 16.7 ° ± 0.2 °, there is at 18.0 ° ± 0.2 ° characteristic peak.
4. crystal formation A according to claim 1 and 2, it is characterised in that its X-ray powder diffraction figure is in 2theta values
20.7 ° ± 0.2 °, 15.1 ° ± 0.2 °, in 18.5 ° ± 0.2 ° one or at two or at three there is characteristic peak.
5. crystal formation A according to claim 4, it is characterised in that its X-ray powder diffraction figure is 20.7 ° in 2theta values
± 0.2 °, 15.1 ° ± 0.2 °, there is at 18.5 ° ± 0.2 ° characteristic peak.
6. the preparation method of a kind of crystal formation A as described in any one of Claims 1 to 5 claim, it is characterised in that described
Crystal formation A is obtained by the following method：By 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine
Solid is added in the single or mixed solvent of alcohols, halogenated hydrocarbon, ether solvent, and volatilization is i.e. available.
7. the preparation method according to right 6, it is characterised in that the solvent is the mixed solvent of dichloromethane and methyl alcohol.
8. a kind of crystal formation C of 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine, its feature exists
In, its X-ray powder diffraction figure 2theta values be 16.1 ° ± 0.2 °, 7.3 ° ± 0.2 °, 6.9 ° ± 0.2 ° place is with feature
Peak.
9. crystal formation C according to claim 8, it is characterised in that its X-ray powder diffraction figure is 14.0 ° in 2theta values
± 0.2 °, in 10.2 ° ± 0.2 ° one or at two there is characteristic peak.
10. crystal formation C according to claim 8 or claim 9, it is characterised in that its X-ray powder diffraction figure is in 2theta values
19.6 ° ± 0.2 °, in 17.3 ° ± 0.2 ° one or at two or with characteristic peak.
A kind of preparation method of 11. crystal formation C as described in any one of claim 8~10 claim, it is characterised in that institute
Crystal formation C is stated to be obtained by the following method：By 5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridine amine
Solid be added in one or more mixed system of alcohols solvent, then to be placed in diffusion under anti-solvent atmosphere i.e. available.
12. preparation method according to right 11, it is characterised in that the anti-solvent is water.
A kind of 13. Pharmaceutical compositions, it is characterised in that：The Pharmaceutical composition is comprising any one of Claims 1 to 5
Crystal formation C and pharmaceutically acceptable auxiliary material any one of crystal formation A or claim 8~10.
Crystal formation any one of a kind of 14. crystal formation A or claim 8~10 as any one of Claims 1 to 5
C is used to prepare the purposes in treating cancer pharmaceutical preparation.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389622A (en) * | 2006-01-20 | 2009-03-18 | 诺瓦提斯公司 | Pyrimidine derivatives used as pi-3 kinase inhibitors |
| CN103476765A (en) * | 2011-02-11 | 2013-12-25 | 达娜-法勃肿瘤研究所公司 | Method of inhibiting hamartoma tumor cells |
| AU2015246141A1 (en) * | 2010-10-01 | 2015-11-12 | Novartis Ag | Manufacturing process for pyrimidine derivatives |
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2016
- 2016-07-08 CN CN201610536514.8A patent/CN106905294A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389622A (en) * | 2006-01-20 | 2009-03-18 | 诺瓦提斯公司 | Pyrimidine derivatives used as pi-3 kinase inhibitors |
| AU2015246141A1 (en) * | 2010-10-01 | 2015-11-12 | Novartis Ag | Manufacturing process for pyrimidine derivatives |
| CN103476765A (en) * | 2011-02-11 | 2013-12-25 | 达娜-法勃肿瘤研究所公司 | Method of inhibiting hamartoma tumor cells |
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