CN108299391A - Crystal form of linatinib 2-maleate and preparation method thereof and pharmaceutical composition - Google Patents
Crystal form of linatinib 2-maleate and preparation method thereof and pharmaceutical composition Download PDFInfo
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- CN108299391A CN108299391A CN201610733806.0A CN201610733806A CN108299391A CN 108299391 A CN108299391 A CN 108299391A CN 201610733806 A CN201610733806 A CN 201610733806A CN 108299391 A CN108299391 A CN 108299391A
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- linatinib
- crystal form
- maleate
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- cancer
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- C—CHEMISTRY; METALLURGY
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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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 present invention relates to the crystal forms of linatinib 2-maleate, and compared with prior art, the crystal form of linatinib 2-maleate of the invention has better solubility in water.The invention further relates to the preparation method of the linatinib 2-maleate crystal form, pharmaceutical composition and its prepare for treat, inhibit and/or the drug of pre- anti-cancer in purposes.
Description
Technical field
This application involves pharmaceutical chemistry crystallization technique fields.Specifically, this application involves linatinib 2-maleates
And its crystal form, with and preparation method thereof, pharmaceutical composition and purposes.
Background technology
Linatinib, English name Neratinib, chemical name are (E)-N- { 4- [3- chloro- 4- (2-) pyridyl group first
Oxygroup) anilino-] -3- cyano -7- ethyoxyl -6- quinolyls } -4- (dimethylamino) -2- crotonamides are a kind of high selections
The HER2 and EGFR inhibitor, chemical structural formula of property are as follows:
Linatinib and its salt can be used for treating cancer, and the cancer includes but not limited to cancer of pancreas, melanoma, lymph
Pipe cancer, carcinoma of parotid gland, Barrett esophagus cancer, cancer of the esophagus, head and neck cancer, oophoroma, breast cancer, Epithelial tumor, major organs such as kidney,
The cancer of bladder, larynx, stomach and lung, polyp of colon and colorectal cancer and prostate cancer.
Patent document US6002008, US6432979 and US6288082, which disclose linatinib, has antitumor activity.
Patent document CN101918390B reports one maleate, Anhydrate object crystal form I of linatinib and monohydrate crystal form
II and preparation method thereof, and disclose XRD, DSC and TGA detection data of linatinib one maleate crystal form I and crystal form II
And spectrogram.
The present inventor is the study found that one maleate, Anhydrate of linatinib obtained according to CN101918390B preparation methods
Object crystal form I in room temperature environment and in water and its is easy to be changed into monohydrate crystal form II.Maleate monohydrate crystal form II
The shortcomings that solubility in room temperature water is less than 1mg/mL, and there are poorly water-solubles easily leads to the biology profit of its solid pharmaceutical preparation
Expenditure is low, drug effect is poor.
Therefore, there is still a need for maleates and its crystal form that exploitation has the linatinib for improving performance for this field, to meet
Strict demand of the pharmaceutical preparation for active constituent.
Invention content
In view of the deficiencies of the prior art, the object of the present invention is to provide the crystal form of novel linatinib 2-maleate with
And their preparation method, pharmaceutical composition and purposes comprising the crystal form.The linatinib 2-maleate of the present invention
Crystal form should have one or more improved characteristics, especially show with preferably water-soluble, higher bioavailability,
Better mobility, better preparation machinability etc..
According to the object of the invention, the present invention provides the crystal form and their preparation method of linatinib 2-maleate.
In a currently preferred embodiment, the crystal form of linatinib 2-maleate of the invention is crystalline state
Linatinib 2-maleate crystal form A.
It is radiated using Cu-K α, the crystal form A of the linatinib 2-maleate is spread out with the X-ray powder that 2 θ angles indicate
Penetrating figure has following characteristics peak：5.1 ± 0.2 °, 6.0 ± 0.2 °, 6.9 ± 0.2 °, 13.2 ± 0.2 °, 18.0 ± 0.2 ° and 22.1
±0.2°。
Preferably, the crystal form A of the linatinib 2-maleate has with the X-ray powder diffraction figure that 2 θ angles indicate
There is following characteristics peak：5.1±0.2°、6.0±0.2°、6.9±0.2°、9.0±0.2°、11.2±0.2°、13.2±0.2°、
13.6 ± 0.2 °, 15.0 ± 0.2 °, 18.0 ± 0.2 °, 21.1 ± 0.2 °, 22.1 ± 0.2 ° and 25.2 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction figure that the crystal form A of the linatinib 2-maleate is indicated with 2 θ angles
With following characteristics peak and its relative intensity：
Without limitation, a representative instance of the crystal form A of the linatinib 2-maleate has as shown in Figure 4
XRPD collection of illustrative plates.
Without limitation, the TGA collection of illustrative plates of the linatinib 2-maleate crystal form A is as shown in Figure 5.
Without limitation, the DSC collection of illustrative plates of the linatinib 2-maleate crystal form A is as shown in Figure 6.
The preparation method of the crystal form A of the linatinib 2-maleate, includes the following steps：It is respectively formed linatinib
Suspension in a solvent and the solution of maleic acid in a solvent, stirring and crystallizing after mixing detach solid, dry, obtain described
The crystal form A of linatinib 2-maleate.Wherein, linatinib is 1 with the molar ratio of reacting of maleic acid:2~1:3, maleic acid
Mass volume ratio with solvent is 50~70mg:1mL, the solvent are selected from C1~C4Alcohol, water, C3~C5Ester, C3~C4Ketone or its
Mixture.
Preferably, the C1~C4Alcohol is isopropanol, C3~C5Ester is ethyl acetate, C3~C4Ketone is acetone.
Preferably, the mass volume ratio of the linatinib and solvent is 50~100mg:1mL.
Preferably, the time of the crystallization is 5~18 hours.
Preferably, the preparation method of the crystal form A of the linatinib 2-maleate carries out at room temperature.
In a currently preferred embodiment, the crystal form of linatinib 2-maleate of the invention is crystalline state
Linatinib 2-maleate crystal form B.
It is radiated using Cu-K α, the crystal form B of the linatinib 2-maleate is spread out with the X-ray powder that 2 θ angles indicate
Penetrating figure has following characteristics peak：6.1 ± 0.2 °, 7.0 ± 0.2 °, 8.3 ± 0.2 °, 11.6 ± 0.2 °, 13.0 ± 0.2 ° and 18.2
±0.2°。
Preferably, the crystal form B of the linatinib 2-maleate has with the X-ray powder diffraction figure that 2 θ angles indicate
There is following characteristics peak：6.1±0.2°、7.0±0.2°、8.3±0.2°、11.6±0.2°、13.0±0.2°、17.0±0.2°、
17.6 ± 0.2 °, 18.2 ± 0.2 °, 21.0 ± 0.2 °, 22.4 ± 0.2 °, 24.7 ± 0.2 ° and 28.0 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction figure that the crystal form B of the linatinib 2-maleate is indicated with 2 θ angles
With following characteristics peak and its relative intensity：
Without limitation, a representative instance of the crystal form B of the linatinib 2-maleate has as shown in Figure 7
XRPD collection of illustrative plates.
Without limitation, the TGA collection of illustrative plates of the crystal form B of the linatinib 2-maleate is as depicted in figure 8.
Without limitation, the DSC collection of illustrative plates of the crystal form B of the linatinib 2-maleate is as shown in Figure 9.
The preparation method of the crystal form B of the linatinib 2-maleate is respectively formed linatinib in a solvent mixed
Suspension and the solution of maleic acid in a solvent, stirring and crystallizing after mixing detach solid, dry, obtain two horse of the linatinib
Carry out the crystal form B of hydrochlorate.Wherein, linatinib is 1 with the molar ratio of reacting of maleic acid:2~1:3, the quality of maleic acid and solvent
Volume ratio is 50~70mg:1mL, the solvent are selected from C3~C4Or mixtures thereof ketone, tetrahydrofuran.
Preferably, the C3~C4Ketone is acetone.
Preferably, the mass volume ratio of the linatinib and solvent is 50~100mg:1mL.
Preferably, the time of the crystallization is 2~3 hours.
Preferably, the preparation method of the crystal form B of the linatinib 2-maleate carries out at room temperature.
In a currently preferred embodiment, the crystal form of linatinib 2-maleate of the invention is crystalline state
Linatinib 2-maleate crystal form C.
It is radiated using Cu-K α, the crystal form C of the linatinib 2-maleate is spread out with the X-ray powder that 2 θ angles indicate
Penetrating figure has following characteristics peak：5.5 ± 0.2 °, 6.5 ± 0.2 °, 8.8 ± 0.2 °, 11.6 ± 0.2 °, 18.0 ± 0.2 ° and 19.7
±0.2°。
Preferably, the crystal form C of the linatinib 2-maleate has with the X-ray powder diffraction figure that 2 θ angles indicate
There is following characteristics peak：5.5±0.2°、6.5±0.2°、8.8±0.2°、11.6±0.2°、13.0±0.2°、15.5±0.2°、
18.0 ± 0.2 °, 19.7 ± 0.2 °, 22.2 ± 0.2 °, 22.8 ± 0.2 °, 24.0 ± 0.2 ° and 28.2 ± 0.2 °.
It is highly preferred that the X-ray powder diffraction figure that the crystal form C of the linatinib 2-maleate is indicated with 2 θ angles
With following characteristics peak and its relative intensity：
Without limitation, a representative instance of the crystal form C of the linatinib 2-maleate has as shown in Figure 10
XRPD collection of illustrative plates.
Without limitation, the TGA collection of illustrative plates of the crystal form C of the linatinib 2-maleate is as shown in figure 11.
Without limitation, the DSC collection of illustrative plates of the crystal form C of the linatinib 2-maleate is as shown in figure 12.
The preparation method of the crystal form C of the linatinib 2-maleate, includes the following steps：It is respectively formed linatinib
Suspension in acetonitrile and solution of the maleic acid in acetonitrile, stirring and crystallizing after mixing detach solid, dry, obtain described
The crystal form C of linatinib 2-maleate.Wherein, linatinib is 1 with the molar ratio of reacting of maleic acid:2~1:3, maleic acid
Mass volume ratio with solvent is 50~70mg:1mL.
Preferably, the mass volume ratio of the linatinib and solvent is 50~100mg:1mL.
Preferably, the time of the crystallization is 2~18 hours.
Preferably, the preparation method of the crystal form C of the linatinib 2-maleate carries out at room temperature.
Compared with one maleate of known linatinib, crystal form A, the crystal form of linatinib 2-maleate of the invention
B and crystal form C has following beneficial property and application effect：
Linatinib 2-maleate crystal form A, crystal form B and the crystal form C of the present invention solubility difference in water at room temperature
For 14mg/mL, 16mg/mL and 8mg/mL, and the anhydride crystal form I and monohydrate crystal form II of one maleate of linatinib exist
The solubility in water is both less than 1mg/mL at room temperature, therefore, linatinib 2-maleate crystal form A, crystal form B and crystalline substance of the invention
Type C all has solubility in better water, and solid pharmaceutical preparation has higher dissolution rate and better bioavilability.
The present inventor also developed the amorphous article and preparation method thereof of one maleate of linatinib under study for action.
Without limitation, a representative instance of the amorphous article has X-ray powder diffraction as shown in Figure 3
(XRPD) collection of illustrative plates, display salt free ligands peak.
The preparation method of the amorphous article, includes the following steps：One maleate of linatinib is formed in a solvent
Solution is concentrated under reduced pressure, and it is wherein described selected from methanol, methanol and C to obtain the unformed of one maleate of the linatinib3~C5Ester
Mixed solvent or methanol and C3~C4The mixed solvent of ketone.
Preferably, the C3~C5Ester is ethyl acetate, the C3~C4Ketone is acetone.
Preferably, a concentration of 10~50mg/mL of the linatinib solution.
Preferably, the reduced pressure vacuum degree is less than 0.09MPa.
Preferably, one maleate solution rotating evaporating temperature of the linatinib is preferably 30~50 DEG C.
In each preparation method of the crystal form of the linatinib 2-maleate of the present invention：Raw material " linatinib " can be
Disclosed linatinib compound, its crystal form or its amorphous article, such as include but not limited to reference to patent document
The linatinib that any one preparation method obtains in CN101918390B.Raw material " one maleate of linatinib " can be
One maleate of disclosed linatinib or its crystal form, such as include but not limited to appoint with reference in patent document CN101918390B
Anticipate a kind of the anhydride crystal form I and monohydrate crystal form II of one maleate of the linatinib that preparation method obtains.These patents
Document is incorporated by way of quoting its full text in the application.
The term used in the present invention has：
" the C3~C5Ester " includes Ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, propyl acetate and propionic acid
Ethyl ester.
" the C3~C4Ketone " includes acetone and butanone, " C1~C4Alcohol " includes methanol, ethyl alcohol, normal propyl alcohol, isopropanol, just
Butanol, sec-butyl alcohol and the tert-butyl alcohol.
" room temperature " refers to 10~30 DEG C.
" stirring " may be used the conventional method of this field, such as agitating mode includes magnetic agitation, mechanical agitation,
Mixing speed is 50~1800 revs/min, preferably 300~900 revs/min.
The conventional method of this field, such as centrifugation or filtering may be used in " separation ".It is preferred that being filtered under diminished pressure, usually
It is filtered at room temperature with the pressure less than atmospheric pressure, preferably pressure is less than 0.09MPa.
Ordinary skill in the art completion may be used in " drying ", such as air drying, forced air drying or decompression are done
It is dry.Dry instrument and method are unrestricted, can be that draught cupboard, convection oven, spray dryer, fluidized bed drying or vacuum are dried
Case；It can depressurize or normal pressure, preferably pressure are less than 0.09MPa.Drying temperature is 10~40 DEG C, and drying time is 10~72 small
When, preferably 2~24 hours, more preferably 2~8 hours.
Heretofore described " crystal form " refers to compound to be confirmed by shown X-ray powder diffraction collection characterization,
There is unique orderly molecules align or configuration in lattice.Well known to those skilled in the art, experimental error therein depends on instrument
Device condition, preparation of samples and sample purity.The 2 θ angles at the peak in XRD spectrum would generally slightly have as instrument is different with sample
It is different.The difference of peak angle degree is according to different instruments, and different samples etc. may differ by 1 °, 0.8 °, 0.5 °, 03 °, 0.1 ° etc., usually
Allowable error ± 0.2 °, so the difference of peak angle degree cannot function as sole criterion.The relative intensity at peak may be with sample, sample system
Standby and other experiment conditions and change, so the sequence of peak intensity cannot function as unique or deciding factor.Height of specimen etc. is real
Peak angle degree overall offset can be caused by testing the influence of factor, allow generally for certain offset.Thus, those skilled in the art can manage
Solution, it is any that there is the crystal form with the same or similar characteristic peak of X-ray powder diffraction pattern of the present invention to belong to the present invention's
Scope." single crystal form " refers to being detected as single crystal form through X-ray powder diffraction.
The crystal form of linatinib 2-maleate of the present invention is pure, single, does not mix any other substantially
Crystal form or amorphous state." do not have substantially " when being used to refer to novel crystal forms in the present invention, refers to this novel crystal forms and account for existing compound
At least 80% (weight), more refer at least 90% (weight), especially at least 95% (weight), (weight that particularly relates at least 99%
Amount).
According to the object of the invention, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition contains treatment, inhibits
And/or prevent the active constituents of medicine of condition effective amount selected from the linatinib salt of the present invention or its crystal form or by present invention system
The linatinib salt or its crystal form that Preparation Method is prepared, and at least one pharmaceutically acceptable carrier or auxiliary agent, wherein
The linatinib salt or its crystal form of the present invention include the amorphous article of one maleate of linatinib, two Malaysia of linatinib
Crystal form A, crystal form B and the crystal form C of hydrochlorate.In addition, described pharmaceutical composition can also include linatinib other officinal salts,
Crystal form or amorphous article.Optionally, described pharmaceutical composition can also include one or more other active constituents of medicine, example
Such as other antiangiogenic agents, cytostatic agent, antiproliferative/antitumor drug.
Including the present invention linatinib maleate and its crystal form pharmaceutical composition and preparation can it is oral, intralesional,
In peritonaeum, intramuscular or intravenous injection；Administered by infusion；By liposome-mediated delivering；Part, intranasal, per anum, warp
Vagina, sublingual, per urethra is percutaneously, intrathecal, through eye or ear delivering administration.A kind of administering mode of the compounds of this invention is unit
Dosage form.Unit dosage form appropriate includes tablet, capsule and the pulvis in pouch or bottle.The crystallization of the present invention
Closing object can be with oral administration.This compound can be 1~6 time with daily administration, more often daily administration 1~4 time.Effective quantity is
It is well known by persons skilled in the art；Effective quantity also according to the form of compound, administering mode and treat the patient's condition severity and
It is fixed.Those skilled in the art can routinely carry out empirical test to measure bioactivity of the compound in biologic test
And thus judge to give suitable dosage.In general, when being about 0.5mg/kg to about 1000mg/kg weight when daily dose, and have
Dosage is imitated when typically about 1mg/kg weight is to about 300mg/kg weight, makes us full using that can be obtained when the compound of the present invention
The result of meaning.
The linatinib maleate and its crystal form of the present invention can be prepared with conventional excipient, such as filler,
Disintegrant, adhesive, lubricant, fumet, color additives and carrier.The carrier can be diluent, and aerosol, part is used
Carrier, aqueous solution, non-aqueous solution or solid.The carrier can be polymer or toothpaste.The carrier of the present invention, which covers, appoints
The pharmaceutically received carrier of what standard, such as phosphate buffered saline solution, acetate buffer saline solution, water, breast
Liquid such as oil/water lotion or triglyceride lotion, various types of wetting agents, tablet, coated tablet and capsule.
If oral or local administration, linatinib maleate of the invention and its crystal form can in different carriers quilt
It is supplied to subject.Usually, this carrier includes excipient such as starch, milk, sugar, certain form of clay, gelatin, tristearin
Acid, talcum, plant fat or oil, natural gum or glycols.Specific carrier is generally basede on required delivering method and is used by selection,
For example, can be used phosphate buffered saline (PBS) (PBS) for the delivering of intravenous or system and usable plant fat, creme, oil
Paste, paste or gelling agent are used for local delivery.
The present invention linatinib maleate and its crystal form can with the treatment appropriate that can be used for neoplasm, inhibit and/
Or diluent, preservative, solubilizer, emulsifier, auxiliary agent and/or the carrier prevented is delivered together.This composition is liquid
Or freeze-dried or dry in other ways preparation.Said preparation includes the diluent containing buffer (for example, Tris-HCl, second
Hydrochlorate, phosphate), pH and ionic strength adjustor, additive such as albumin or gelatin to be to prevent Surface absorption, surface-active
Agent (for example, polysorbate20, polysorbate20, Pluronic F-68, bile salt), solubilizer are (for example, glycerine, poly-
Ethylene glycol), antioxidant (for example, ascorbic acid, sodium metasulfite), preservative is (for example, thimerosal, benzyl alcohol, para hydroxybenzene
Formate ester), incremental agent or tension regulator (for example, lactose, mannitol), polymer such as polyethylene glycol, contain metal ion
Compound or the compound is introduced in or on the granular preparation of hydrogel or liposome, microemulsion, micella, single layer or
Multi-layer vesicles.This composition will influence physical state, solubility, stability, the internal rate of release of compound or composition
With internal clearance rate.The selection of composition will be according to the different and different of the physics of compound and chemical property.
The linatinib maleate and its crystal form of the present invention can also carry out local delivery by capsule, and the capsule allows
Sustained release occurs within a certain period of time for compound.Controlled release or sustained-release composition are included in lipophilic depots (example
Such as, aliphatic acid, wax, oil) in preparation.
The linatinib maleate and its crystal form of the present invention can also be beneficial to the reactive compound of cancer patient with others
Such as other chemical reagent or antibiotic substance are administered by dosage together, or used with radiation therapy in combination.These activations
Dosage administration can be carried out simultaneously or successively with the compound of the present invention by closing object.The compound of the present invention can be also configured to same
Comprising other reactive compounds in dosage unit, for example, the two can be comprised in piller, tablet or a capsule.It can be with
The reactive compound for some possible types that the compound of the present invention is used in combination be mitotic inhibitor such as taxol and
Vincaleukoblastinum, alkylating agent such as cis-platinum and cyclophosphamide, antimetabolite such as 5 FU 5 fluorouracil, fluorouracil and hydroxycarbamide, DNA are embedding
Enter agent such as adriamycin and bleomycin, topoisomerase enzyme inhibitor such as Etoposide and camptothecine, anti-angiogenic agent is all
Such as angiostatin and antiestrogen such as tamoxifen.
Description of the drawings
XRPD collection of illustrative plates of the Fig. 1 with reference to the CN101918390B one maleate, Anhydrate object crystal form I of linatinib prepared
XRPD collection of illustrative plates of the Fig. 2 with reference to the CN101918390B one maleate monohydrate crystal form II of linatinib prepared
The XRPD collection of illustrative plates of the amorphous article of Fig. 3 one maleates of linatinib of the present invention
The XRPD collection of illustrative plates of the crystal form A of Fig. 4 linatinib 2-maleates of the present invention
The TGA collection of illustrative plates of the crystal form A of Fig. 5 linatinib 2-maleates of the present invention
The DSC collection of illustrative plates of the crystal form A of Fig. 6 linatinib 2-maleates of the present invention
The XRPD collection of illustrative plates of the crystal form B of Fig. 7 linatinib 2-maleates of the present invention
The TGA collection of illustrative plates of the crystal form B of Fig. 8 linatinib 2-maleates of the present invention
The DSC collection of illustrative plates of the crystal form B of Fig. 9 linatinib 2-maleates of the present invention
The XRPD collection of illustrative plates of the crystal form C of Figure 10 linatinib 2-maleates of the present invention
The TGA collection of illustrative plates of the crystal form C of Figure 11 linatinib 2-maleates of the present invention
The DSC collection of illustrative plates of the crystal form C of Figure 12 linatinib 2-maleates of the present invention
Specific embodiment
It will be helpful to further understand the present invention by following embodiments, but be not used in limitation present disclosure.
Detecting instrument and method：
X-ray powder diffraction (XRPD)：Instrument is Bruker D8Advance diffractometer.Sample is in room temperature
Lower test.Testing conditions are as follows, angular range：3~40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：0.2 second/step.
Differential thermal analysis data are picked up from TA Instruments Q200MDSC.Detection method is：Take 1~10 milligram of sample
Product are positioned in closed aperture aluminium crucible, and N is dried in 40mL/min with the heating rate of 10 DEG C/min2Protection under by sample from
Room temperature.
Thermogravimetric analysis data is picked up from TA Instruments Q500TGA.Detection method is：The sample of 5~15mg is taken to put
It is placed in platinum crucible, by the way of being segmented high resolution detection, N is dried in 40mL/min with the heating rate of 10 DEG C/min2
Protection under by sample from room temperature.
Nucleus magnetic hydrogen spectrum data (1HNMR it) picks up from Bruker Avance II DMX 400MHZ nuclear magnetic resonance chemical analysers.Claim
1~5mg samples are measured, is dissolved into nuclear-magnetism sample cell and is detected with about 0.5mL deuterated reagents.
Various reagents used in embodiment are commercially available purchase unless otherwise instructed.
It is ambient operation unless otherwise instructed in embodiment.
Preparation example 1The preparation of one maleate monohydrate crystal form II of linatinib
One maleate of linatinib, one water is prepared with reference to the method for embodiment 1 in patent document CN101918390B
Object crystal form II is closed, concrete operations are as follows：By crude product (E)-N- { 4- [the chloro- 4- of 3- (2- pyridinyl methoxies) anilino-] -3- cyanogen
Base -7- ethyoxyl -6- quinolyls } -4- (dimethylamino) -2- crotonamides free alkali (0.100kg, 0.159 mole) uses USP
10% solution (0.082kg, 0.10L) rinsing of the purified water in normal propyl alcohol, is then added water: normal propyl alcohol solution (0.74kg,
0.90L).Maleic acid (0.0191kg, 0.164 mole) is added and by 10% water of mixture: normal propyl alcohol (0.082kg, 0.10L)
Rinsing.Mixture is heated rapidly to 50-60 DEG C and is kept at least 15 minutes, until obtaining solution.Hot solution is set to pass through
Being preheating to 50-60 DEG C of 0.2Mm filter cylinders makes its clarification, and collects filtrate in the 2L multinecked flasks for being preheating to 45-55 DEG C.It will filter
Cylinder 10% water for being preheating to 45-55 DEG C: normal propyl alcohol (0.082kg, 0.10L) rinsing.Solution is cooled at least 1 hour
40 DEG C and at such a temperature keep 12 hours, room temperature (25 DEG C) is then cooled at least 4 hours and is kept at such a temperature
At least 2 hours.Mixture is filtered 5 minutes on the Buchner funnel of 12.5cm diameters, then with pre-filtered 10% water: just
Propanol solution (2x0.12kg, 2x 0.15L) rinses and washing.Filter cake is compacted and keeps suction until dropping liquid stops substantially, is gone through
When about 1 hour.
Its XRPD collection of illustrative plates is as shown in Fig. 2, one maleic acid of linatinib that display is reported with patent document CN101918390B
The XRPD collection of illustrative plates of salt monohydrate crystal form II is consistent.
Preparation example 2The preparation of one maleate, Anhydrate object crystal form I of linatinib
One maleate, Anhydrate of linatinib is prepared with reference to the method for embodiment 2 in patent document CN101918390B
Object crystal form I, concrete operations are as follows：Product (II types) derived from preparation example 1 is dry (50 DEG C, 10mmHg, for 24 hours), obtain 94.4g
The crystallization of (88% yield), i.e., anhydrous (E)-N- { 4- [the chloro- 4- of 3- (2- pyridinyl methoxies) anilino-] -3- cyano -7- ethoxies
Base -6- quinolyls } -4- (dimethylamino) -2- crotonamides maleate (I types).
Its XRPD collection of illustrative plates is as shown in Figure 1, one maleic acid of linatinib that display is reported with patent document CN101918390B
The XRPD collection of illustrative plates of salt anhydride crystal form I is consistent.
After testing, in room temperature environment and water in and its be easy to be changed into monohydrate crystal form II.
Embodiment 1
One maleate, Anhydrate object crystal form I of 20mg linatinib is taken, 1.5mL methanol, 50 DEG C of ultrasonic dissolved clarifications, 30 DEG C of water-baths are added
Under be concentrated to dryness, obtain the amorphous article of one maleate of 18mg linatinib.XRPD collection of illustrative plates is as shown in Figure 3.
Embodiment 2
One maleate, Anhydrate object crystal form I of 200mg linatinib is taken, 15mL methanol, 50 DEG C of ultrasonic dissolved clarifications, 30 DEG C of water-baths are added
Under be concentrated to dryness, obtain the amorphous article of one maleate of 190mg linatinib.
Embodiment 3
One maleate, Anhydrate object crystal form I of 20mg linatinib is taken, 1mL methanol and 0.5mL ethyl acetate, 50 DEG C of ultrasounds are added
Dissolved clarification is concentrated to dryness under 30 DEG C of water-baths, obtains the amorphous article of one maleate of 17mg linatinib.
Embodiment 4
One maleate, Anhydrate object crystal form I of 20mg linatinib is taken, adds 1.2mL methanol and 0.3mL acetone, 50 DEG C of ultrasounds molten
Clearly, it is concentrated to dryness under 30 DEG C of water-baths, obtains the amorphous article of one maleate of 18mg linatinib.
Embodiment 5
30mg linatinib is taken, is disperseed with 0.4mL isopropanols, is added while stirring dissolved with 14mg maleic acids at room temperature
The solution of 0.2mL isopropanols obtains yellow clear solution, is precipitated after stirring, obtains yellow slurry, stirs 5 hours, filtering, room
Temperature vacuum drying 2 hours, obtains the crystal form A of 32mg linatinib 2-maleates, yield 75%.
1H NMR(400MHz,DMSO-d6):δ 9.79 (s, 1H), 9.72 (s, 1H), 8.94 (s, 1H), 8.60 (d, J=
4.6Hz, 1H), 8.53 (s, 1H), 7.88 (t, J=7.7Hz, 1H), 7.59 (d, J=7.9Hz, 1H), 7.40 (d, J=
16.1Hz, 3H), 7.30-7.18 (m, 2H), 6.77 (s, 2H), 6.16 (s, 4H), 5.29 (s, 2H), 4.33 (q, J=7.0Hz,
2H), 3.96 (d, J=4.5Hz, 2H), 2.81 (s, 6H), 1.47 (t, J=7.0Hz, 3H), 1.24 (s, 1H).Testing result table
It is bright：Linatinib is about 1 with molar ratio with maleic acid in the crystal form A of linatinib 2-maleate:2 at salt.
XRPD collection of illustrative plates is as shown in Figure 4.
TGA collection of illustrative plates is as shown in Figure 5：The crystal form A decomposition temperatures of the linatinib 2-maleate are about 154.7 DEG C.
DSC collection of illustrative plates is as shown in Figure 6：The crystal form A fusing points of the linatinib 2-maleate are about 148.2 DEG C.
After testing, solubility of the crystal form A of linatinib 2-maleate at room temperature in water is about 14mg/mL.
Embodiment 6
30mg linatinib is taken, is disperseed with 0.6mL ethyl acetate, is added while stirring is dissolved with 14mg maleic acids at room temperature
0.2mL ethyl acetate solution, obtain yellow clear solution, be precipitated after stirring, obtain yellow slurry, stir 5 hours, mistake
Filter, room temperature in vacuo are dried 2 hours, and the crystal form A of 30mg linatinib 2-maleates, yield 71% are obtained.
Embodiment 7
300mg linatinib is taken, is disperseed with 3mL isopropanols, is added while stirring dissolved with 138mg maleic acids at room temperature
The solution of 2.76mL isopropanols obtains yellow clear solution, is precipitated after stirring, obtains yellow slurry, stirs 18 hours, filtering,
Room temperature in vacuo is dried 4 hours, and the crystal form A of 400mg linatinib 2-maleates, yield 94% are obtained.
Embodiment 8
300mg linatinib is taken, is disperseed with 4mL acetone, is added while stirring dissolved with 138mg maleic acids at room temperature
The solution of 3mL acetone obtains yellow clear solution, is precipitated after stirring, obtains yellow slurry, stirs 18 hours, filtering, and room temperature is true
Sky is 2 hours dry, obtains the crystal form A of 409mg linatinib 2-maleates, yield 96%.
Embodiment 9
Solvent in embodiment 8 is replaced by below table and can get that crystal form A for replacing Buddhist nun's 2-maleate.
There is same or analogous XRPD collection of illustrative plates, DSC to scheme for the sample that embodiment 6~9 is prepared and the sample of embodiment 5
Spectrum, TGA collection of illustrative plates (not shown) illustrate that 6~9 sample of embodiment and the sample of embodiment 5 are identical crystal forms.
Embodiment 10
30mg linatinib is taken, is disperseed with 0.6mL acetone, is added while stirring dissolved with 14mg maleic acids at room temperature
The solution of 0.2mL acetone obtains yellow clear solution, is precipitated after stirring, obtains yellow slurry, stirs 2 hours, filtering, room temperature
Vacuum drying 2 hours, obtains 30mg linatinib 2-maleate crystal form B, yield 70.5%.
1H NMR(400MHz,DMSO-d6):δ 9.78 (s, 1H), 9.70 (s, 1H), 8.94 (s, 1H), 8.60 (d, J=
5.0Hz, 1H), 8.52 (s, 1H), 7.88 (t, J=7.9Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 7.40 (d, J=
15.6Hz, 3H), 7.30-7.18 (m, 2H), 6.77 (s, 2H), 6.14 (s, 4H), 5.29 (s, 2H), 4.33 (q, J=7.0Hz,
2H), 3.96 (d, J=4.7Hz, 2H), 2.81 (s, 6H), 1.47 (t, J=7.0Hz, 3H), 1.23 (s, 1H).Testing result table
It is bright：Linatinib is about 1 with molar ratio with maleic acid in the crystal form B of linatinib 2-maleate:2 at salt.
XRPD collection of illustrative plates is as shown in Figure 7.
TGA collection of illustrative plates is as shown in Figure 8：The decomposition temperature of the crystal form B of the linatinib 2-maleate is about 166.4 DEG C.
DSC collection of illustrative plates is as shown in Figure 9：The decomposition temperature of the crystal form B of the linatinib 2-maleate is about 173.6 DEG C.
After testing, solubility of the crystal form B of linatinib 2-maleate at room temperature in water is about 16mg/mL.
Embodiment 11
30mg linatinib is taken, is disperseed with 0.4mL tetrahydrofurans, is added while stirring is dissolved with 14mg maleic acids at room temperature
0.25mL tetrahydrofurans solution, obtain yellow clear solution, be precipitated after stirring, obtain yellow slurry, stir 3 hours, mistake
Filter, room temperature in vacuo are dried 2 hours, and the crystal form B of 33mg linatinib 2-maleates, yield 78% are obtained.
Embodiment 12
300mg linatinib is taken, is disperseed with 3mL tetrahydrofurans, is added while stirring is dissolved with 138mg maleic acids at room temperature
2.76mL tetrahydrofurans solution, obtain yellow clear solution, be precipitated after stirring, obtain yellow slurry, stir 3 hours, mistake
Filter, room temperature in vacuo are dried 4 hours, and the crystal form B of 407mg linatinib 2-maleates, yield 93% are obtained.
Embodiment 13
Solvent in embodiment 12 is replaced by below table and can get that crystal form B for replacing Buddhist nun's 2-maleate.
Sample that embodiment 11~13 is prepared and the sample of embodiment 10 have same or analogous XRPD collection of illustrative plates,
DSC collection of illustrative plates, TGA collection of illustrative plates (not shown) illustrate that 11~13 sample of embodiment and the sample of embodiment 10 are identical crystal forms.
Embodiment 14
30mg linatinib is taken, is disperseed with 0.6mL acetonitriles, is added while stirring dissolved with 14mg maleic acids at room temperature
The solution of 0.2mL acetonitriles obtains yellow clear solution, is precipitated after stirring, obtains yellow slurry, stirs 2 hours, filtering, room temperature
Vacuum drying 2 hours, obtains 30mg linatinib 2-maleate crystal form C, yield 71%.
1H NMR(400MHz,DMSO-d6):δ 9.78 (s, 1H), 9.71 (s, 1H), 8.94 (s, 1H), 8.60 (d, J=
4.8Hz, 1H), 8.52 (s, 1H), 7.88 (dd, J=8.7,6.9Hz, 1H), 7.59 (d, J=7.9Hz, 1H), 7.40 (d, J=
16.4Hz, 3H), 7.30-7.18 (m, 2H), 6.76 (d, J=7.0Hz, 2H), 6.16 (s, 4H), 5.29 (s, 2H), 4.33 (q, J
=7.0Hz, 2H), 3.99-3.93 (m, 2H), 2.81 (s, 6H), 1.47 (t, J=6.9Hz, 3H), 1.23 (s, 1H).Detection knot
Fruit shows：Linatinib is about 1 with molar ratio with maleic acid in the crystal form C of linatinib 2-maleate:2 at salt.
XRPD collection of illustrative plates is as shown in Figure 10.
TGA collection of illustrative plates is as shown in figure 11：The decomposition temperature of the crystal form C of the linatinib 2-maleate is about 147.3 DEG C.
DSC collection of illustrative plates is as shown in figure 12：The fusing point of the crystal form C of the linatinib 2-maleate is about 157.6 DEG C
After testing, solubility of the crystal form C of linatinib 2-maleate at room temperature in water is about 8mg/mL.
Embodiment 15
300mg linatinib is taken, is disperseed with 3mL acetonitriles, the 2.76mL second dissolved with 138mg is added while stirring at room temperature
The solution of nitrile obtains yellow clear solution, is precipitated after stirring, obtains yellow slurry, stirs 18 hours, filtering, and room temperature in vacuo is dry
Dry 4 hours, obtain the crystal form C of 403mg linatinib 2-maleates, yield 95%.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
Those skilled in the art within the technical scope disclosed by the invention, can without the variation that creative work is expected or
It replaces, should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be limited with claims
Subject to fixed protection domain.
Claims (15)
1. the crystal form A of structural formula linatinib 2-maleate as follows,
It is characterized in that, being radiated using Cu-K α, the crystal form A of the linatinib 2-maleate is penetrated with the X- that 2 θ angles indicate
Line powder diagram has following characteristics peak：5.1±0.2°、6.0±0.2°、6.9±0.2°、13.2±0.2°、18.0±
0.2 ° and 22.1 ± 0.2 °.
2. the crystal form A of linatinib 2-maleate according to claim 1, which is characterized in that the linatinib two
The crystal form A of maleate has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles indicate：5.1±0.2°、6.0±
0.2°、6.9±0.2°、9.0±0.2°、11.2±0.2°、13.2±0.2°、13.6±0.2°、15.0±0.2°、18.0±
0.2 °, 21.1 ± 0.2 °, 22.1 ± 0.2 ° and 25.2 ± 0.2 °.
3. the crystal form A of linatinib 2-maleate according to claim 2, which is characterized in that the linatinib two
The crystal form A of maleate has following characteristics peak and its relative intensity with the X-ray powder diffraction figure that 2 θ angles indicate：
4. the preparation method of the crystal form A of any one of claims 1 to 3 linatinib 2-maleate, including following step
Suddenly：It is respectively formed the suspension of linatinib in a solvent and the solution of maleic acid in a solvent, stirring and crystallizing after mixing, separation
Solid, it is dry, obtain the crystal form A of the linatinib 2-maleate.Wherein, linatinib and maleic acid react molar ratio
It is 1:2~1:3, the mass volume ratio of maleic acid and solvent is 50~70mg:1mL, the solvent are selected from C1~C4Alcohol, water, C3~
C5Ester, C3~C4Or mixtures thereof ketone；
Preferably, the C1~C4Alcohol is isopropanol, C3~C5Ester is ethyl acetate, C3~C4Ketone is acetone；
Preferably, the mass volume ratio of the linatinib and solvent is 50~100mg:1mL；
Preferably, the time of the stirring and crystallizing is 5~18 hours；
Preferably, the preparation method of the crystal form A of the linatinib 2-maleate carries out at room temperature.
5. the crystal form B of structural formula linatinib 2-maleate as follows,
It is characterized in that, being radiated using Cu-K α, the crystal form B of the linatinib 2-maleate is penetrated with the X- that 2 θ angles indicate
Line powder diagram has following characteristics peak：6.1±0.2°、7.0±0.2°、8.3±0.2°、11.6±0.2°、13.0±
0.2 ° and 18.2 ± 0.2 °.
6. the crystal form B of linatinib 2-maleate according to claim 5, which is characterized in that the linatinib two
The crystal form B of maleate has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles indicate：6.1±0.2°、7.0±
0.2°、8.3±0.2°、11.6±0.2°、13.0±0.2°、17.0±0.2°、17.6±0.2°、18.2±0.2°、21.0±
0.2 °, 22.4 ± 0.2 °, 24.7 ± 0.2 ° and 28.0 ± 0.2 °.
7. the crystal form B of linatinib 2-maleate according to claim 6, which is characterized in that the linatinib two
The crystal form B of maleate has following characteristics peak and its relative intensity with the X-ray powder diffraction figure that 2 θ angles indicate：
8. the preparation method of the crystal form B of any one of claim 5~7 linatinib 2-maleate, including following step
Suddenly：It is respectively formed the suspension of linatinib in a solvent and the solution of maleic acid in a solvent, stirring and crystallizing after mixing, separation
Solid, it is dry, obtain the crystal form B of the linatinib 2-maleate.Wherein, linatinib and maleic acid react molar ratio
It is 1:2~1:3, the mass volume ratio of maleic acid and solvent is 50~70mg:1mL, the solvent are selected from C3~C4Ketone, tetrahydrochysene furan
Or mixtures thereof mutter；
Preferably, the C3~C4Ketone is acetone；
Preferably, the mass volume ratio of the linatinib and solvent is 50~100mg:1mL；
Preferably, the time of the stirring and crystallizing is 2~3 hours；
Preferably, the preparation method of the crystal form B of the linatinib 2-maleate carries out at room temperature.
9. the crystal form C of structural formula linatinib 2-maleate as follows,
It is characterized in that, being radiated using Cu-K α, the crystal form C of the linatinib 2-maleate is penetrated with the X- that 2 θ angles indicate
Line powder diagram has following characteristics peak：5.5±0.2°、6.5±0.2°、8.8±0.2°、11.6±0.2°、18.0±
0.2 ° and 19.7 ± 0.2 °.
10. the crystal form C of linatinib 2-maleate according to claim 9, which is characterized in that the linatinib two
The crystal form C of maleate has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles indicate：5.5±0.2°、6.5±
0.2°、8.8±0.2°、11.6±0.2°、13.0±0.2°、15.5±0.2°、18.0±0.2°、19.7±0.2°、22.2±
0.2 °, 22.8 ± 0.2 °, 24.0 ± 0.2 ° and 28.2 ± 0.2 °.
11. the crystal form C of linatinib 2-maleate according to claim 10, which is characterized in that the linatinib
The crystal form C of 2-maleate has following characteristics peak and its relative intensity with the X-ray powder diffraction figure that 2 θ angles indicate：
12. the preparation method of the crystal form C of any one of claim 9~11 linatinib 2-maleate, including it is following
Step：It is respectively formed suspension of the linatinib in acetonitrile and solution of the maleic acid in acetonitrile, stirring and crystallizing after mixing is divided
It is dry from solid, obtain the crystal form C of the linatinib 2-maleate.Wherein, linatinib and maleic acid react mole
Than being 1:2~1:3, the mass volume ratio of maleic acid and solvent is 50~70mg:1mL；
Preferably, the mass volume ratio of the linatinib and solvent is 50~100mg:1mL；
Preferably, the time of the stirring and crystallizing is 2~18 hours；
Preferably, the preparation method of the crystal form C of the linatinib 2-maleate carries out at room temperature.
13. a kind of pharmaceutical composition, it includes treatment, inhibition and/or prevention condition effective amounts in Claims 1 to 4
Two Malaysia of linatinib described in any one of any one of them linatinib 2-maleate crystal form A, claim 5~8
The crystal form B of hydrochlorate, the crystal form C of the linatinib 2-maleate described in any one of claim 9~12, and it is at least one
Pharmaceutically acceptable carrier or auxiliary agent.
14. pharmaceutical composition according to claim 13, which is characterized in that described pharmaceutical composition is the medicine being administered orally
Object dosage form, including tablet, capsule, granule, powder, pill, pastille, pulvis, solution, syrup, suspension, breast
Agent and elixir.
It is any in claim 5~8 15. the crystal form A of linatinib 2-maleate according to any one of claims 1 to 4
The crystal form B of linatinib 2-maleate described in, two maleic acid of linatinib described in any one of claim 9~13
Pharmaceutical composition described in any one of the crystal form C of salt or claim 13~14 is being prepared for treating, inhibiting and/or prevent
Application in the drug of cancer；The cancer at least one selected from the following：Cancer of pancreas, melanoma, lymphatic vessel cancer, carcinoma of parotid gland, bar
Thunder spy's cancer of the esophagus, cancer of the esophagus, head and neck cancer, oophoroma, breast cancer, Epithelial tumor, major organs such as kidney, bladder, larynx, stomach and lung
Cancer, polyp of colon and colorectal cancer and prostate cancer.
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