CN106810490A - A kind of crystal formation of biaryl compound and its preparation method and application - Google Patents
A kind of crystal formation of biaryl compound and its preparation method and application Download PDFInfo
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- CN106810490A CN106810490A CN201710066336.1A CN201710066336A CN106810490A CN 106810490 A CN106810490 A CN 106810490A CN 201710066336 A CN201710066336 A CN 201710066336A CN 106810490 A CN106810490 A CN 106810490A
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- HUNGUWOZPQBXGX-UHFFFAOYSA-N O=C(Cc(cc1)ncc1-c(cc1)ccc1OCCN1CCOCC1)NCc1ccccc1 Chemical compound O=C(Cc(cc1)ncc1-c(cc1)ccc1OCCN1CCOCC1)NCc1ccccc1 HUNGUWOZPQBXGX-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The crystal formation of the biaryl compound with formula (I) structure provided the invention provides a kind of crystal formation of biaryl compound and its preparation method and application, the present invention, uses CuKαRadiation, has diffraction maximum with the powder x-ray diffraction that 2 θ angles are represented 4.16 ± 0.5,12.53 ± 0.5,16.75 ± 0.5,18.33 ± 0.5,21.00 ± 0.5,21.50 ± 0.5,25.35 ± 0.5；By test result indicate that, the crystal-form compound that the present invention is provided has good stability, and with relatively good dissolubility.
Description
Technical field
The present invention relates to crystal formation field, more particularly to a kind of crystal formation of biaryl compound and its preparation method and application.
Background technology
It is directed in the signal transduction pathway (such as growth of cell, differentiation, survival, migration etc.) of various normal cells
Kinases, kinases is considered as being played a role in various diseases and obstacle.Maximum group is protein kinase in kinases, its effect
In specific protein and correct the activity of the specified protein.They are widely used in the transmission and control of signal
Intracellular complicated reaction.Protein tyrosine kinase (PTK) can be divided into two species, membrane receptor protein EGFR-TK
(e.g., growth factor receptor protein EGFR-TK) and non-receptor protein tyrosine kinase are (e.g., in proto-oncogene product
Src families).In various human cancers, the overactivity of Src, including colon cancer, breast cancer, lung cancer, bladder are reported
Cancer, cutaneum carcinoma and stomach cancer etc..Because in many human tumor types, formation, development and the transfer of tumour are directed to
Overactivity (in the absence of variation), thus suggestion recently using Src as treatment of cancer general target spot.
Biaryl compound, chemical name is：2- (5- (4- (2- beautiful jades base oxethyl) phenyl) gives a tongue-lashing pyridine -2- bases)-N- benzene
Methyl acetamide, researches and develops code KX-01, KX2-391, with structure shown in formula I.
Compound K X2-391 is disclosed in patent CN10118473B, US7300931B, and discloses it in treatment cell
Application in terms of proliferative disorders.KX2-391 and its pharmaceutically acceptable salt are effective Src tyrosine kinase inhibitors,
Disease and the disorder by Src kinase regulatories can effectively be treated.GI50s of the KX2-391 in cancerous cell line is 9-60nM, mesh
It is preceding in the clinical II phases.
There is polymorphism in KX2-391.Polymorphism refers to same compound by the generation bar for controlling its different
Part, can form two or more molecule space arrangement mode, so as to produce the phenomenon of different solid crystals, sameization
The different crystal forms of compound, its chemical composition is identical, but microcosmic crystal structure is different, thus results in them in mode of appearance, physics and chemistry
Had differences in property and bioactivity.Polymorphism directly affects the preparation processing performance of medicine, and can influence medicine
Stability, solubility and bioavilability, and then have influence on quality, security, validity and its application of medicine.Therefore,
In drug research and development, the polymorphic problem of medicine should be comprehensively considered.At present, KX2-391 studies it comprehensively still in development
Solid form, the research and development and approval listing to KX2-391 are significant.
The content of the invention
In view of this, the technical problems to be solved by the invention are the crystal formation and its system for providing a kind of biaryl compound
It is steady that Preparation Method and application, the crystal formation of the biaryl compound with formula (I) structure that the present invention is provided, and the crystal formation have had
The qualitative dissolubility become reconciled.
The invention provides the crystal formation of biaryl compound of the one kind with formula (I) structure, CuK is usedαRadiation, with 2 θ angles
The powder x-ray diffraction for representing is spent 4.16 ± 0.5,12.53 ± 0.5,16.75 ± 0.5,18.33 ± 0.5,21.00 ± 0.5,
21.50 ± 0.5,25.35 ± 0.5 have diffraction maximum；
Preferably, the DSC collection of illustrative plates of the crystal formation has endothermic peak at 126.9 DEG C and 137.4 DEG C.
The present invention also provides a kind of preparation side of the crystal formation of the biaryl compound with formula (I) structure of the present invention
Method, including：
1) mixed liquor will be obtained with the biaryl compound of formula (I) structure and solvent mixed dissolution,
The solvent is the alcohol of C1~C4, the chloralkane of C1~C2, ethyl acetate, Ethyl formate, diethyl malonate,
One or more in tetrahydrofuran, acetone, butanone, DMF and DMSO；
2) to anti-solvent is added dropwise in mixed liquor, crystallization obtains the biaryl compound with formula (I) structure of crystal formation；
The anti-solvent is one or more in water, the alkane of C5~C9, isopropyl ether and methyl tertiary butyl ether(MTBE).
Preferably, the biaryl compound and the amount ratio of the solvent are 1g: (2~50) mL.
Preferably, the biaryl compound and the amount ratio of the anti-solvent are 1g: (10~70) mL.
Preferably, the temperature of the crystallization is -5~40 DEG C.
Present invention also offers the mixing crystal formation of biaryl compound of the one kind with formula (I) structure, including institute of the present invention
The biaryl compound with formula (I) structure of the crystal formation stated.
Present invention also offers a kind of Src tyrosine kinase inhibitor compositions, including crystal formation of the present invention tool
There are the biaryl compound of formula (I) structure or the diaryl chemical combination with formula (I) structure of mixing crystal formation of the present invention
Thing, and pharmaceutically acceptable excipient.
Preferably, the formulation of the inhibitor be pulvis, granule, tablet, capsule, pill, paste, sustained release preparation or
Controlled release preparation.
Preferably, the excipient is wetting agent, dispersant, pH adjusting agent, antioxidant, filler, diluent, lubrication
Agent, solubilizer, suspending agent, flavouring, adhesive, disintegrant, osmotic pressure regulator, flocculant, antiplastering aid, suspending agent, emulsification
One or more in agent and preservative.
Compared with prior art, the invention provides the crystal formation of biaryl compound of the one kind with formula (I) structure, use
CuKαRadiation, the powder x-ray diffraction represented with 2 θ angles 4.16 ± 0.5,12.53 ± 0.5,16.75 ± 0.5,18.33 ±
0.5,21.00 ± 0.5,21.50 ± 0.5,25.35 ± 0.5 have diffraction maximum；By test result indicate that, the present invention provide crystalline substance
Type compound has good stability, and with relatively good dissolubility.
Brief description of the drawings
Fig. 1 is the XRPD figures of the crystal formation biaryl compound with formula (I) structure that the embodiment of the present invention 1 is prepared
Spectrum；
Fig. 2 is the DSC collection of illustrative plates that the embodiment of the present invention 1 prepares the crystal formation biaryl compound with formula (I) structure；
Fig. 3 is the TGA collection of illustrative plates of the crystal formation biaryl compound with formula (I) structure that the embodiment of the present invention 1 is prepared.
Specific embodiment
The invention provides the crystal formation of biaryl compound of the one kind with formula (I) structure, CuK is usedαRadiation, with 2 θ angles
The powder x-ray diffraction for representing is spent 4.16 ± 0.5,12.53 ± 0.5,16.75 ± 0.5,18.33 ± 0.5,21.00 ± 0.5,
21.50 ± 0.5,25.35 ± 0.5 have diffraction maximum；
More specifically, the crystal formation of the biaryl compound with formula (I) structure of the present invention, uses CuKαRadiation, with 2
The powder x-ray diffraction that θ angles are represented is 2.10 ± 0.5,4.16 ± 0.5,6.24 ± 0.5,8.33 ± 0.5,12.53 ± 0.5,
16.75±0.5、18.33±0.5、19.05±0.5、19.85±0.5、21.00±0.5、21.50±0.5、21.92±0.5、
23.16 ± 0.5,25.35 ± 0.5 have diffraction maximum；
More specifically, the crystal formation of the biaryl compound with formula (I) structure of the present invention, uses CuKαRadiation, with 2
The powder x-ray diffraction that θ angles are represented is 2.10 ± 0.5,3.68 ± 0.5,4.16 ± 0.5,6.24 ± 0.5,8.33 ± 0.5,
12.53±0.5、16.26±0.5、16.75±0.5、18.33±0.5、19.05±0.5、19.85±0.5、21.00±0.5、
21.50±0.5、21.92±0.5、22.50±0.5、23.16±0.5、25.08±0.5、25.35±0.5、25.70±0.5、
27.49 ± 0.5,29.67 ± 0.5,33.97 ± 0.5,38.43 ± 0.5 have diffraction maximum；
Specifically, the detail parameters of the X-ray diffraction of the biaryl compound with formula (I) structure of the present invention are shown in
Table 1, shows as diffraction maximum position：2 θ values (°)；Diffraction maximum relative intensity：Peak height value (Height%).
Table 1 has the X-ray diffraction result of the biaryl compound of formula (I) structure
It should be understood that 2 θ values of X-ray powder diffraction figure can be varied slightly between machine or between sample, its numerical value can
About 0.5 unit, or about 0.4 unit of difference, or about 0.3 unit of difference can be differed, or difference is about
0.2 unit, or about 0.1 unit of difference, therefore cited numerical value can not be construed to absolute value.Should equally manage
Solution, size about 5 units of equally possible difference of peak height, or about 4 units of difference, or about 3 units of difference,
Or about 2 units of difference, or about 1 unit of difference, therefore it is strong to be included in the XRPD traces (trace) in the present invention
Spend for illustrative, be not meant for definitely comparing.
Preferably, the crystal formation of the biaryl compound with formula (I) structure that the present invention is provided, uses CuKαSpoke
Penetrate, the powder x-ray diffraction represented with 2 θ angles is 2.10 ± 0.4,4.16 ± 0.4,6.24 ± 0.4,8.33 ± 0.4,12.53
±0.4、16.75±0.4、18.33±0.4、19.05±0.4、19.85±0.4、21.00±0.4、21.50±0.4、21.92
± 0.4,23.16 ± 0.4,25.35 ± 0.4 have diffraction maximum；
Preferably, the crystal formation of the biaryl compound with formula (I) structure that the present invention is provided, uses CuKαSpoke
Penetrate, the powder x-ray diffraction represented with 2 θ angles is 2.10 ± 0.3,4.16 ± 0.3,6.24 ± 0.3,8.33 ± 0.3,12.53
±0.3、16.75±0.3、18.33±0.3、19.05±0.3、19.85±0.3、21.00±0.3、21.50±0.3、21.92
± 0.3,23.16 ± 0.3,25.35 ± 0.3 have diffraction maximum；
Preferably, the crystal formation of the biaryl compound with formula (I) structure that the present invention is provided, uses CuKαSpoke
Penetrate, the powder x-ray diffraction represented with 2 θ angles is 2.10 ± 0.2,4.16 ± 0.2,6.24 ± 0.2,8.33 ± 0.2,12.53
±0.2、16.75±0.2、18.33±0.2、19.05±0.2、19.85±0.2、21.00±0.2、21.50±0.2、21.92
± 0.2,23.16 ± 0.2,25.35 ± 0.2 have diffraction maximum；
Preferably, the crystal formation of the biaryl compound with formula (I) structure that the present invention is provided, uses CuKαSpoke
Penetrate, the powder x-ray diffraction represented with 2 θ angles is 2.10 ± 0.1,4.16 ± 0.1,6.24 ± 0.1,8.33 ± 0.1,12.53
±0.1、16.75±0.1、18.33±0.1、19.05±0.1、19.85±0.1、21.00±0.1、21.50±0.1、21.92
± 0.1,23.16 ± 0.1,25.35 ± 0.1 have diffraction maximum；
Additionally, the present invention is also analyzed described novel crystal forms by differential canning calorimetry, differential is being used
Scanning Calorimetric Techniques are when being analyzed, and show as when there are 2 endothermic peaks point in the DSC collection of illustrative plates that heating rate is 12 DEG C per minute
Not at 126.9 DEG C ± 1 DEG C and 137.4 DEG C ± 1 DEG C, its spectrogram is as shown in Figure 2.
It should be understood that may have the deviation there is similar situation, differential canning calorimetry with X-ray powder diffraction figure numerical value
Cited numerical value can not be construed to absolute value.
Present invention also offers the preparation of the crystal formation of one kind biaryl compound with formula (I) structure of the present invention
Method, including：
1) mixed liquor will be obtained with the biaryl compound of formula (I) structure and solvent mixed dissolution,
The solvent is the alcohol of C1~C4, the chloralkane of C1~C2, ethyl acetate, Ethyl formate, diethyl malonate,
One or more in tetrahydrofuran, acetone, butanone, DMF and DMSO；
2) to anti-solvent is added dropwise in mixed liquor, crystallization obtains the biaryl compound with formula (I) structure of crystal formation；
The anti-solvent is one or more in water, the alkane of C5~C8, isopropyl ether and methyl tertiary butyl ether(MTBE).
According to the present invention, mixed liquor will be obtained with the biaryl compound of formula (I) structure and solvent mixed dissolution；Its
In, the solvent is preferably methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, dichloromethane, chloroform, 1,2- dichloroethanes, second
One or more in acetoacetic ester, Ethyl formate, diethyl malonate, tetrahydrofuran, acetone, butanone, DMF and DMSO；It is described
The temperature of mixed dissolution is preferably 10~40 DEG C, more preferably 20~30 DEG C；The use of the biaryl compound and the solvent
Amount ratio preferably 1g: (2~50) mL, more preferably 1g: (3~40) mL, most preferably 1g: (5~30) mL.
According to the present invention, the present invention also to being added dropwise anti-solvent in mixed liquor, crystallization, obtain crystal formation with formula (I) structure
Biaryl compound；Wherein, the anti-solvent is preferably the one kind in water, heptane, hexane, isopropyl ether and methyl tertiary butyl ether(MTBE)
Or it is several.The biaryl compound is preferably 1g: (10~70) mL, more preferably 1g: (20 with the amount ratio of the anti-solvent
~30) mL, most preferably 1g: (40~60) mL；The temperature that anti-solvent is added dropwise is preferably 20~50 DEG C, more preferably 25~
40℃；The crystallization is preferably stirring and crystallizing；The temperature of the crystallization is preferably -5~40 DEG C, more preferably 10~30 DEG C；This
Invention also includes that will cool down the biaryl compound for separating out separates with solvent, the method for the separation be preferably solid filter or from
The heart is separated；Present invention additionally comprises the biaryl compound drying of the crystal formation of the present invention for obtaining separation of solid and liquid, the drying
Temperature be preferably 40~70 DEG C, preferably 50~60 DEG C；The present invention does not have particular/special requirement, art technology to dry instrument
The known instrument for drying solid of personnel.
Present invention also offers the mixing crystal formation of biaryl compound of the one kind with formula (I) structure, including institute of the present invention
The biaryl compound with formula (I) structure of the crystal formation stated.
Present invention also offers a kind of Src tyrosine kinase inhibitor compositions, including crystal formation of the present invention tool
There are the biaryl compound of formula (I) structure or the diaryl chemical combination with formula (I) structure of mixing crystal formation of the present invention
Thing, and pharmaceutically acceptable excipient.
In the present invention, the excipient refers to the additives in addition to main ingredient, alternatively referred to as auxiliary material in pharmaceutical preparation.Such as
Binder, filler in tablet, disintegrant, lubricant；Wine, vinegar, concoction in medicine pill etc.；Semisolid preparation ointment
Base portion in agent, creme；Preservative, antioxidant in liquid preparation, flavouring, aromatic, cosolvent, emulsifying agent, increasing
Solvent, osmotic pressure regulator, colouring agent etc. can be described as excipient, specific to the present invention, it is preferred that excipient of the present invention
For wetting agent, dispersant, pH adjusting agent, antioxidant, filler, diluent, lubricant, solubilizer, suspending agent, flavouring, viscous
One or more in mixture, disintegrant, osmotic pressure regulator, flocculant, antiplastering aid, suspending agent, emulsifying agent and preservative, more
One or more preferably in filler, diluent, lubricant, disintegrant, wetting agent and adhesive, it is highly preferred that filling
Agent is preferably one or more in starch, microcrystalline cellulose, lactose and calcium monohydrogen phosphate；The lubricant is preferably stearic acid
Magnesium, talcum powder or silica；One kind or several in the disintegrant such as dried starch, sodium carboxymethylcellulose and PVPP
Kind；Described adhesive is preferably one or more in starch paste, methylcellulose, hydroxy propyl cellulose and gelatin.
In the present invention, the formulation of the inhibitor is preferably pulvis, granule, tablet, capsule, pill paste, sustained release
Preparation or controlled release preparation, more preferably tablet or capsule.
The invention provides the crystal formation of biaryl compound of the one kind with formula (I) structure, CuK is usedαRadiation, with 2 θ angles
The powder x-ray diffraction for representing is spent 4.169 ± 0.5,12.539 ± 0.5,16.759 ± 0.5,18.339 ± 0.5,21.009
± 0.5,21.509 ± 0.5,25.359 ± 0.5 have diffraction maximum；By test result indicate that, the present invention provide crystal-form compound
With good stability, and with relatively good dissolubility.
Technical scheme below in conjunction with the embodiment of the present invention is clearly and completely described, it is clear that described implementation
Example is only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, this area is common
The every other embodiment that technical staff is obtained under the premise of creative work is not made, belongs to the model of present invention protection
Enclose.
Embodiment 1
2- (5- (4- (2- beautiful jades base oxethyl) phenyl) pyridine -2- bases)-N- benzyls-acetamide (KX2-391) crystal formation
The preparation of (i.e. with the crystal formation biaryl compound of formula (I) structure, subsequent embodiment is referred to as KX2-391 crystal formation B)
KX2-391 (5.0g) is placed in 500ml round-bottomed flasks, methyl alcohol 150ml is added, dissolves KX2-391 complete, put
In stirring at 50 DEG C.Purified water 300ml is gradually added dropwise, gained slurry, is stirred at room temperature 1h crystallizations after completion of dropping, suction filtration,
50 DEG C of vacuum drying, gained solid is KX2-391 crystal formations B.HPLC detects purity >=99.83%.
The preparation of the KX2-391 crystal formations B of embodiment 2
KX2-391 (5.0g) is placed in 100ml round-bottomed flasks, DMSO 25ml are added, dissolves KX2-391 complete, put
Stir at room temperature.Purified water 50ml is gradually added dropwise, gained slurry after completion of dropping stirs 1h crystallizations, suction filtration, 50 at 0 DEG C
DEG C vacuum drying, gained solid is KX2-391 crystal formations B.HPLC detects purity >=99.81%.
The preparation of the KX2-391 crystal formations B of embodiment 3
KX2-391 (5.0g) is placed in 250ml round-bottomed flasks, dichloromethane 15ml is added, KX2-391 has been dissolved
Entirely, stirred at being placed in 30 DEG C.Normal heptane 100ml is gradually added dropwise, gained slurry after completion of dropping is stirred at room temperature 0.5h analysis
Crystalline substance, suction filtration, 50 DEG C of vacuum drying, gained solid is KX2-391 crystal formations B.HPLC detects purity >=99.80%.
The preparation of the KX2-391 crystal formations B of embodiment 4
KX2-391 (2.0g) is placed in 500ml round-bottomed flasks, acetone 100ml is added, dissolves KX2-391 complete, put
Stir at room temperature.N-hexane 150ml is gradually added dropwise, gained slurry after completion of dropping stirs 1h crystallizations, suction filtration, 50 at 0 DEG C
DEG C vacuum drying, gained solid is KX2-391 crystal formations B.HPLC detects purity >=99.79%.
The preparation of the KX2-391 crystal formations B of embodiment 5
KX2-391 (2.0g) is placed in 250ml round-bottomed flasks, THF 50ml are added, dissolves KX2-391 complete, put
In stirring at 40 DEG C.Methyl tertiary butyl ether(MTBE) 100ml is gradually added dropwise, gained slurry, is stirred at room temperature 2h crystallizations after completion of dropping,
Suction filtration, 50 DEG C of vacuum drying, gained solid is KX2-391 crystal formations B.HPLC detects purity >=99.81%.
The detection of the KX2-391 crystal formations B of embodiment 6
KX2-391 crystal formations B obtained in Example 1, is detected using XRPD methods to it.The instrument and equipment used is
RIGAKU TTR type III X-ray powder diffraction instrument, condition determination and method：Cu (target), 40KV-30mA (operating voltage and electricity
Stream), 2 θ=2~50 degree (sweep limits), 4.0deg/min. (sweep speed), the collection of illustrative plates for obtaining is shown in Fig. 1, as shown in Figure 1, real
Apply example 1 offer KX2-391 crystal formations B XRPD collection of illustrative plates 2 θ ± 0.2 ° be 2.10,3.68,4.16,6.24,8.33,12.53,
16.26、16.75、18.33、19.05、19.85、21.00、21.50、21.92、22.50、23.16、25.08、25.35、
25.70th, there is peak 27.49,29.67,33.97,38.43 position.
The crystal formation B that the present invention additionally uses the KX2-391 that DSC-TGA methods are provided the present invention is detected.Use
Instrument and equipment is the TGA-DSC of plum Teller-support benefit, detects 22 DEG C of environmental condition, relative humidity RH68%, temperature range 0-
400 DEG C, heating rate 12 DEG C/min, protective gas N2, the collection of illustrative plates for obtaining is shown in Fig. 2 and Fig. 3.As shown in Figure 2, embodiment 1 is provided
KX2-391 crystal formations B DSC collection of illustrative plates at 126.9 DEG C, 137.4 DEG C have endothermic peak.From the figure 3, it may be seen that the KX2- that embodiment 1 is provided
The TGA collection of illustrative plates of 391 crystal formation B is at 200 DEG C in the past without substantially weightless.
Stability and the dissolubility detection of the KX2-391 crystal formations B of embodiment 7
The raw material KX2-391 that the KX2-391 crystal formations B and embodiment that Example 1 is provided are provided carries out stability test.
The normal storage temperature of KX2-391 is -20 DEG C.The KX2-391 crystal formations B that embodiment 1 is provided is in 25 DEG C of temperature, relative humidity
Lucifuge storage is sealed under conditions of RH60%, accelerated stability experiment is carried out.Determine at 0 month, 1 month, 2 months and 3 months
Moisture, purity, maximum single impurity content and total impurities content, result of the test is shown in Table 2.
The stability test of the KX2-391 crystal formations B of table 2
As can be seen from the table, the KX2-391 crystal formations B that embodiment 1 is provided has preferable stability.
Dissolubility test is carried out by KX2-391 crystal formation B and the KX2-391 raw materials obtained to the present invention, be the results are shown in Table
3；
Table 3
Wherein, it is almost insoluble：Solute 1g (ml), can not be completely dissolved in solvent 10000ml；Slightly soluble：Solute 1g (ml),
Can be dissolved in solvent 100~less than 1000ml；It is slightly molten：Solute 1g (ml), can dissolve in solvent 30~less than 100ml；Easily
Hold：Solute 1g (ml), can dissolve in solvent 1~less than 10ml.
From table 3 it can be seen that the dissolubility of crystal formation B is compared with raw material, its dissolubility in ethyl acetate and ethanol compared with
It is good.
The explanation of above example is only intended to help and understands the method for the present invention and its core concept.It should be pointed out that right
For those skilled in the art, under the premise without departing from the principles of the invention, the present invention can also be carried out
Some improvement and modification, these are improved and modification is also fallen into the protection domain of the claims in the present invention.
Claims (10)
1. one kind has the crystal formation of the biaryl compound of formula (I) structure, it is characterised in that use CuKαRadiation, with 2 θ angle tables
The powder x-ray diffraction for showing 4.16 ± 0.5,12.53 ± 0.5,16.75 ± 0.5,18.33 ± 0.5,21.00 ± 0.5,
21.50 ± 0.5,25.35 ± 0.5 have diffraction maximum；
2. the crystal formation of the biaryl compound with formula (I) structure according to claim 1, it is characterised in that the crystalline substance
The DSC collection of illustrative plates of type has endothermic peak at 126.9 DEG C and 137.4 DEG C.
3. the preparation side of the crystal formation of the biaryl compound with formula (I) structure described in a kind of claim 1~2 any one
Method, including：
1) mixed liquor will be obtained with the biaryl compound of formula (I) structure and solvent mixed dissolution,
The solvent is alcohol, the chloralkane of C1~C2, ethyl acetate, Ethyl formate, diethyl malonate, the tetrahydrochysene of C1~C4
One or more in furans, acetone, butanone, DMF and DMSO；
2) to anti-solvent is added dropwise in mixed liquor, crystallization obtains the biaryl compound with formula (I) structure of crystal formation；
The anti-solvent is one or more in water, the alkane of C5~C9, isopropyl ether and methyl tertiary butyl ether(MTBE).
4. preparation method according to claim 3, it is characterised in that the consumption of the biaryl compound and the solvent
Than being 1g: (2~50) mL.
5. preparation method according to claim 3, it is characterised in that the use of the biaryl compound and the anti-solvent
Amount is than being 1g: (10~70) mL.
6. preparation method according to claim 3, it is characterised in that the temperature of the crystallization is -5~40 DEG C.
7. one kind has the mixing crystal formation of the biaryl compound of formula (I) structure, including described in claim 1~2 any one
Crystal formation the biaryl compound with formula (I) structure.
8. a kind of Src tyrosine kinase inhibitor compositions, including crystal formation described in Claims 1 to 5 any one has
The diaryl chemical combination with formula (I) structure of the mixing crystal formation described in the biaryl compound or claim 6 of formula (I) structure
Thing, and pharmaceutically acceptable excipient.
9. Src tyrosine kinase inhibitor compositions according to claim 8, it is characterised in that the agent of the inhibitor
Type is pulvis, granule, tablet, capsule, pill, paste, sustained release preparation or controlled release preparation.
10. Src tyrosine kinase inhibitor compositions according to claim 8, it is characterised in that the excipient is profit
Humectant, dispersant, pH adjusting agent, antioxidant, filler, diluent, lubricant, solubilizer, suspending agent, flavouring, adhesive,
One or more in disintegrant, osmotic pressure regulator, flocculant, antiplastering aid, suspending agent, emulsifying agent and preservative.
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| EP4302831A1 (en) | 2022-07-04 | 2024-01-10 | Trifarma S.p.A. | Process for synthesis of tirbanibulin |
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