CN109963846A - A kind of crystal form of 2-maleate of tyrosine kinase inhibitor and preparation method thereof - Google Patents
A kind of crystal form of 2-maleate of tyrosine kinase inhibitor and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title abstract description 5
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title abstract description 5
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 title abstract description 5
- 239000002904 solvent Substances 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 21
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- 238000000034 method Methods 0.000 claims description 16
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- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical group FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 1
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- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 3
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
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- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
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- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
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- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D401/14—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 three or more hetero rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to crystal forms of 2-maleate of a kind of tyrosine kinase inhibitor and preparation method thereof.Specifically, the present invention relates to a kind of IV crystal forms of 2-maleate and preparation method thereof of EGF-R ELISA (EGFR) inhibitor.IV crystal form has good chemical stability and stability of crystal form, can be preferably applied to clinical treatment.
Description
The present invention relates to crystal forms of 2-maleate of tyrosine kinase inhibitor and preparation method thereof.
Studies have shown that being more than that 50% proto-oncogene and oncoprotein all have tyrosine kinase activity, their unconventionality expression will lead to tumour.Tyrosine kinase inhibitor was listed since 2001, it has also become a kind of new antitumor drug of sudden emergence.
EGF-R ELISA (EGFR) is a member of receptor tyrosine kinase family, EGF-R ELISA access plays a very important role during tumorigenesis, has become one of most important research and development target spot of therapeutic field of tumor at present.Such drug through listing has Erlotinib (erlotinib), Gefitinib (gefitinib) and Lapatinib (lapatinb, Tykerb, GW572016).
WO2011029265A1 (publication date 2011.03.17) discloses a kind of EGF-R ELISA (EGFR) inhibitor, entitled (the R of its chemistry, E)-N- (4- (the chloro- 4- of 3- (pyridine -2- ylmethoxy) phenyl amino) -3- cyano -7- ethoxyquinoline -6- base) -3- (1- methylpyrrole alkyl -2- base) acrylamide, the drug molecule has apparent medicine generation, drug effect advantage, shown in structure such as formula (II):
The I crystal of the 2-maleate of compound shown in WO2014008794A1 (publication date 2014.01.16) open formula (II), shown in the structure of the salt such as formula (I):
Crystalline structure as medicinal active ingredient often influences the chemically and physically stability of the drug, and the difference of crystallization condition and condition of storage is likely to result in the variation of the crystal structure of compound, sometimes can also be along with the crystal form for generating other forms.In general, unbodied drug products do not have well-regulated crystal structure, often poor with other defects, such as product stability, and it is more difficult to filter, and easily agglomerate, poor fluidity etc..Therefore, we have found IV crystal form again on the basis of I crystal.
Summary of the invention
The technical problem to be solved in the present invention is to provide one kind (R, E) IV crystal form and preparation method thereof of-N- (4- (the chloro- 4- of 3- (pyridine -2- ylmethoxy) phenyl amino) -3- cyano -7- ethoxyquinoline -6- base) -3- (1- methylpyrrole alkyl -2- base) acrylamide 2-maleate (as shown in formula (I)), which has good stability.
Technical scheme is as follows:
The present invention provides a kind of IV crystal form of compound shown in formula (I), it is characterized by: being radiated using Cu-K α, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it has characteristic peak at 6.2,6.4,9.0,10.3,11.4,18.1,19.1,20.8,22.0,23.6 and 25.1, error range can be ± 0.3, ± 0.2 or ± 0.1
Preferably, IV crystal form has characteristic peak at 6.2,6.4,9.0,10.3,11.4,12.5,18.1,19.1,20.8,22.0,23.6,24.3,25.1,25.7,26.9,27.7, and error range can be ± 0.3, ± 0.2 or ± 0.1.
More preferably, IV crystal form has characteristic peak at 6.21,6.45,9.02,9.84,10.26,11.41,12.50,16.16,16.66,18.10,19.14,20.76,22.03,22.60,23.58,24.27,25.14,25.71,26.92,27.69,29.41 and 31.56, and error range can be ± 0.3, ± 0.2 or ± 0.1.
The present invention also provides a kind of methods for preparing IV crystal form, which is characterized in that the method is selected from:
(1) compound shown in formula (I) is dissolved in good solvent, anti-solvent, crystallization, filtering, up to IV crystal form of target after drying is added；The good solvent is selected from alcohols solvent, and the alcohols solvent is selected from methanol, ethyl alcohol or isopropanol, and the anti-solvent is selected from ether solvent, and the ether solvent is selected from Isosorbide-5-Nitrae-dioxane；The method of the crystallization is selected from room temperature crystallization, cooling crystallization, solvent flashing crystallization or crystal seed induction crystallization is added；
(2) compound shown in formula (I) is added in solvent, is beaten, filtering, up to IV crystal form of target after drying；The solvent is selected from the mixed solvent of alcohols and ethers, the preferred methanol of the alcohols solvent, ethyl alcohol or isopropanol, the preferred Isosorbide-5-Nitrae-dioxane of ether solvent.
The invention further relates to the pharmaceutical composition of IV crystal form, described pharmaceutical composition is made of IV crystal form and pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to the pharmaceutical compositions of IV crystal form, IV crystal form to treat and/or prevent the purposes in the drug of disease related with protein kinase or illness in preparation, the protein kinase is selected from EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase, the disease or illness are selected from cancer, the preferred lung cancer of the cancer, breast cancer, epidermis squamous carcinoma or gastric cancer.
By the way that X-ray powder diffraction collection (XRPD), differential scanning calorimetric analysis (DSC) carry out structure determination to IV crystal form of compound shown in acquired formula (I), crystal form is studied.
The method of crystal form recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, anti-solvent crystallization is added after being dissolved in organic solvent with compound shown in raw material formula (I), after the completion of crystallization, through filtration drying, required crystallization can be obtained.
The method of crystallization of the present invention has room temperature crystallization, cooling crystallization, solvent flashing crystallization, is added crystal seed induction crystallization etc., and the temperature of the cooling is selected from 40 DEG C hereinafter, it is preferred that -10 DEG C to 40 DEG C, can also stir in the Crystallization Process.
Starting material used in crystal form preparation method of the present invention can be compound shown in any form of formula (I), and concrete form includes but is not limited to: unformed, any crystal form etc..
Detailed description of the invention
In the description and claims of this application, unless otherwise stated, Science and Technology noun used herein has the normally understood meaning of those skilled in the art institute.However, for a better understanding of the present invention, the definition and explanation of part relational language is provided below.In addition, with the definition of term provided herein and being construed to quasi- when the definition of term provided herein and explanation and the inconsistent normally understood meaning of those skilled in the art.
" halogen or halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atom, iodine atom etc..
" C of the present invention
1-6The alkyl containing 1-6 carbon atom of alkyl " expression linear chain or branched chain, specific example includes but is not limited to: methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2- methyl butyl, neopentyl, 1- ethyl propyl, n-hexyl, isohesyl, 3- methyl amyl, 2- methyl amyl, 1- methyl amyl, 3, 3- dimethylbutyl, 2, 2- dimethylbutyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2, 3- dimethylbutyl, 2- ethyl-butyl, 1, 2- dimethyl propyl etc..
" alcohols solvent " of the present invention refers to one or more " hydroxyl " substitution " C
1-6Group derived from one or more hydrogen atoms on alkyl ", " C
1-6As defined hereinabove, specific example includes but is not limited to alkyl ": methanol, ethyl alcohol, isopropanol, normal propyl alcohol, n-butanol, isoamyl alcohol or trifluoroethanol.
" ether solvent " of the present invention refers to the chain compound or cyclic compound that containing ehter bond-O- and carbon atom number is 1 to 10, and specific example includes but is not limited to: tetrahydrofuran, ether, propylene glycol monomethyl ether, methyl tertiary butyl ether(MTBE) or Isosorbide-5-Nitrae-dioxane.
" anti-solvent " of the present invention refers to low to the solvability of molecule (or solute), poor or insoluble；By the way that good solvent to be used in combination with anti-solvent, to reduce the dissolubility of object to be crystallized in a solvent；Since anti-solvent is in conjunction with good solvent, the dissolubility of molecule (or solute) is reduced, so that molecule (or solute) precipitation be made to form solid phase, solid is then filtered out from liquid phase, then separate two kinds of solvents, the crystal of target can be obtained.
" X-ray powder diffraction collection or XRPD " of the present invention refer to according to bragg's formula 2d sin θ=n λ (in formula, λ be X-ray wavelength,
The series n of diffraction is any positive integer, generally take first-order diffraction peak, n=1), when X-ray is with the sweep angle θ (complementary angle of incidence angle, also known as Bragg angle) when being incident on a certain atomic plane with d lattice plane spacing of crystal or partial crystals sample, it is just able to satisfy Bragg equation, to measure this group of X-ray powder diffraction figure.
" differential scanning calorimetric analysis or DSC " of the present invention refers in sample heating or thermostatic process, temperature difference, differential heat flow between measurement sample and reference substance, to characterize all physical changes related with fuel factor and chemical change, the transformation information of sample is obtained.
" 2 θ or 2 θ angles " of the present invention refer to the angle of diffraction, and θ is Bragg angle, and unit is ° or degree, the error range of 2 θ are ± 0.1~± 0.5, preferably ± 0.1~± 0.3, more preferably ± 0.2.
" interplanar distance or interplanar distance (d value) " of the present invention refers to that space lattice selects the unit vector a of the two neighboring lattice point of connection of 3 irrelevancy rows, b, c, dot matrix is divided into juxtaposed parallelepiped unit, referred to as interplanar distance by them.Space lattice is divided according to determining parallelepiped unit line, obtains a set of rectilinear grid, referred to as space lattice or lattice.Dot matrix and lattice are respectively the different crystal faces with the periodicity of the Points And lines of geometry reflection crystal structure, and interplanar distance (the distance between parallel crystal face of i.e. adjacent two) is different；Unit is
Or angstrom.
The invention further relates to, IV crystal form including formula (I) compound represented, and the pharmaceutical composition of optional one or more pharmaceutical carriers and/or diluent.Pharmaceutically acceptable any dosage form can be made in described pharmaceutical composition.For example, IV crystal form or pharmaceutical preparation of formula (I) compound represented of the invention can be formulated as tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection, injection sterile powder and concentrated solution for injection), suppository, inhalant or spray.
In addition, pharmaceutical composition of the present invention can also be with any suitable administration mode, such as the modes such as oral, parenteral, rectum, transpulmonary or local administration are applied to the patient or subject for needing this treatment.When for when being administered orally, described pharmaceutical composition to can be made into oral preparation, such as oral solid formulation, such as tablet, capsule, pill, granule；Or, oral liquid, such as oral solution, oral suspensions, syrup.When oral preparation is made, the pharmaceutical preparation also may include suitable filler, adhesive, disintegrating agent, lubricant etc..When being used for parenteral administration, the pharmaceutical preparation can be made into injection, including injection, injection sterile powder and concentrated solution for injection.When injection is made, the conventional method in existing pharmaceutical field is can be used to be produced in described pharmaceutical composition.When preparing injection, additives can be added without in the pharmaceutical preparation, suitable additives can also be added according to the property of drug.When being used for rectally, the pharmaceutical preparation can be made into suppository etc..When for transpulmonary administration, the pharmaceutical preparation can be made into inhalant or spray etc..In certain preferred aspects, IV crystal form of formula of the invention (I) compound represented is to treat and/or prevention effective dose is present in pharmaceutical composition or drug.In certain preferred aspects, IV crystal form of formula (I) compound represented of the present invention is present in pharmaceutical composition or drug in the form of unit dose.
Formula (I) compound of the present invention, its IV crystal form can be used for preparing the purposes in the drug for the treatment of disease related with protein kinase or illness.Therefore, the application further relates to, and IV crystal form of formula (I) compound of the present invention is used to prepare the purposes of drug, and the drug is used to treat the purposes in the drug of disease related with protein kinase.Furthermore, the application further relates to, a method of inhibiting disease related with protein kinase comprising to IV crystal form or pharmaceutical composition of the invention of subject with this need application treatment and/or the formula (I) compound of the present invention of prevention effective dose.
In certain preferred aspects, the disease is cancer, the preferred lung cancer of the cancer, breast cancer, epidermis squamous carcinoma or gastric cancer.
Advantageous effect of the invention
Compared with prior art, technical solution of the present invention has the advantage that
Research has shown that IV crystal form favorable solubility of compound shown in formula (I) prepared by the present invention, purity are higher, under conditions of high temperature, high humidity, illumination crystal form do not change through XRPD detection, stability of crystal form it is good；IV crystal form of compound shown in the formula (I) that technical solution of the present invention obtains can satisfy the medicinal requirements of production and transport storage, and stable processing technique repeats controllably, can adapt in industrialized production.
Fig. 1 is the XRPD map of compounds Ⅳ crystal form shown in formula (I).
Fig. 2 is the DSC map of compounds Ⅳ crystal form shown in formula (I).
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is only used to illustrate the technical scheme of the present invention, and non-limiting the spirit and scope of the invention.
Experiment test equipment used
1, differential scanning calorimeter (Differential Scanning Calorimeter, DSC)
Instrument model: Mettler Toledo DSC 3
+STAR
e System
Purge gass: nitrogen
Heating rate: 10.0 DEG C/min
Temperature range: 25-350
2, x-ray diffraction pattern (X-ray Powder Diffraction, XRPD)
Instrument model: Bruker D8Discover A25X- ray powder diffractometer
Ray: monochromatic Cu-K alpha ray (λ=1.5406)
Scanning mode: the θ of θ/2, scanning range: 10-48 °
Voltage: 40KV, electric current: 40mA
Compound (free state) shown in formula (II) is referring to the method preparation in patent application WO2011029265A1 (publication date 2011.03.17)；
Compound (2-maleate) shown in formula (I) is referring to the method preparation in patent application WO2014008794A1 (publication date 2014.01.16).
The preparation of embodiment 1, IV crystal form
Take (R, E)-N- (4- (the chloro- 4- of 3- (pyridine -2- ylmethoxy) phenyl amino) -3- cyano -7- ethoxyquinoline -6- base) -3- (1- methylpyrrole alkyl -2- base) acrylamide 2-maleate (0.5g) is added in reaction flask, methanol (5mL) is added to be stirred to dissolve, acquired solution system is added slowly with stirring 1,4- dioxane, until there is a large amount of muddy appearance, filter cake is collected after persistently stirring 5h, vacuum drying, obtain product, yield 91%.The X-ray powder diffraction spectrogram (XRPD map) of the crystallized sample is shown in that Fig. 1, DSC spectrogram are shown in Fig. 2, has sharp melting endothermic peak at about 127.7 DEG C, this crystal form is defined as IV crystal form, 2 θ characteristic peak positions are as shown in the table:
Table 1, IV crystal form characteristic peak
The preparation of embodiment 2, IV crystal form
Take (R, E)-N- (4- (the chloro- 4- of 3- (pyridine -2- ylmethoxy) phenyl amino) -3- cyano -7- ethoxyquinoline -6- base) -3- (1- methylpyrrole alkyl -2- base) acrylamide 2-maleate (20mg) is added in reaction flask, methanol and 1 is added, mixed solvent (the v/v=1:1 of 4- dioxane, 200 μ L), it is heated to 50 DEG C, mashing stirring 72h, collect filter cake, vacuum drying, product, yield 93% are obtained, which is determined as IV crystal form through X-ray powder diffraction detection.
Claims (7)
- IV crystal form of compound shown in formula (I), it is characterized by: being radiated using Cu-K α, obtain the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction, it has characteristic peak at 6.2,6.4,9.0,10.3,11.4,18.1,19.1,20.8,22.0,23.6 and 25.1
- IV crystal form as described in claim 1, it is characterized in that, it is radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, has characteristic peak at 6.2,6.4,9.0,10.3,11.4,12.5,18.1,19.1,20.8,22.0,23.6,24.3,25.1,25.7,26.9 and 27.7.
- IV crystal form as described in claim 1, it is characterized in that, it is radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angle of the angle of diffraction is obtained, has characteristic peak at 6.21,6.45,9.02,9.84,10.26,11.41,12.50,15.62,16.16,16.66,17.62,18.10,19.14,20.76,21.39,22.03,22.60,23.58,24.27,25.14,25.71,26.92,27.69,29.41 and 31.56.
- IV crystal form according to any one of claim 1-3, wherein the 2 θ angle error range is ± 0.20.
- A method of preparing IV crystal form as described in any one of claim 1-4, which is characterized in that the method is selected from:(1) compound shown in formula (I) is dissolved in good solvent, anti-solvent, crystallization, filtering, up to IV crystal form of target after drying is added；The good solvent is selected from alcohols solvent, and the alcohols solvent is selected from methanol, ethyl alcohol or isopropanol, and the anti-solvent is selected from ether solvent, and the ether solvent is selected from Isosorbide-5-Nitrae-dioxane；The method of the crystallization is selected from room temperature crystallization, cooling crystallization, solvent flashing crystallization or crystal seed induction crystallization is added；(2) compound shown in formula (I) is added in solvent, is beaten, filtering, up to IV crystal form of target after drying；The solvent is selected from the mixed solvent of alcohols and ethers, the preferred methanol of the alcohols solvent, ethyl alcohol or isopropanol, the preferred Isosorbide-5-Nitrae-dioxane of ether solvent.
- A kind of pharmaceutical composition, described pharmaceutical composition are made of IV crystal form of any of claims 1-4 with pharmaceutically acceptable carrier, diluent or excipient.
- Purposes of the pharmaceutical composition described in described in any item IV crystal forms of claim 1-4, claim 5 in the drug of preparation treatment and/or prevention disease related with protein kinase or illness, the protein kinase is selected from EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase, the disease or illness are selected from cancer, the preferred lung cancer of the cancer, breast cancer, epidermis squamous carcinoma or gastric cancer.
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| CN201710667478 | 2017-08-07 | ||
| CN201710667478.3 | 2017-08-07 | ||
| PCT/CN2018/098950 WO2019029477A1 (en) | 2017-08-07 | 2018-08-06 | Crystal form of dimaleate of tyrosine kinase inhibitor and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020639A (en) * | 2009-09-14 | 2011-04-20 | 上海恒瑞医药有限公司 | 6-amido quinazoline or 3-cyano quinoline derivative, preparation method thereof and application of derivative to medicament |
| CN103539783A (en) * | 2012-07-12 | 2014-01-29 | 江苏恒瑞医药股份有限公司 | I-type crystal of dimaleate of tyrosine kinase inhibitor and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020639A (en) * | 2009-09-14 | 2011-04-20 | 上海恒瑞医药有限公司 | 6-amido quinazoline or 3-cyano quinoline derivative, preparation method thereof and application of derivative to medicament |
| CN103539783A (en) * | 2012-07-12 | 2014-01-29 | 江苏恒瑞医药股份有限公司 | I-type crystal of dimaleate of tyrosine kinase inhibitor and preparation method thereof |
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