CN111138414A - Crystal form of tyrosine kinase inhibitor and preparation method thereof - Google Patents
Crystal form of tyrosine kinase inhibitor and preparation method thereof Download PDFInfo
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- CN111138414A CN111138414A CN201911064120.7A CN201911064120A CN111138414A CN 111138414 A CN111138414 A CN 111138414A CN 201911064120 A CN201911064120 A CN 201911064120A CN 111138414 A CN111138414 A CN 111138414A
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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
- C07D401/14—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a crystal form of a tyrosine kinase inhibitor and a preparation method thereof. Specifically, the invention relates to a crystal form of a compound shown as a formula (I) and a preparation method thereof. The novel crystal form has good stability and can be better used for clinical treatment.
Description
Technical Field
The invention relates to a crystal form of a tyrosine kinase inhibitor and a preparation method thereof.
Background
Studies have shown that over 50% of proto-oncogenes and oncogene products have tyrosine kinase activity and that aberrant expression thereof leads to tumorigenesis. Tyrosine kinase inhibitors have been marketed since 2001 and have become a new class of anticancer agents of the heteroplasmon process.
Epidermal Growth Factor Receptor (EGFR) is a member of receptor tyrosine kinase family, and the receptor pathway of EGFR plays a very important role in the process of tumor occurrence and development, and has become one of the most important research and development targets in the field of tumor therapy. Such drugs are now marketed as erlotinib, gefitinib and lapatinb, Tykerb, GW 572016.
WO2011029265 discloses an Epidermal Growth Factor Receptor (EGFR) inhibitor, the chemical name of which is (R, E) -N- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -3-cyano-7-ethoxyquinolin-6-yl) -3- (1-methylpyrrolidinyl-2-yl) acrylamide, the drug molecule has significant pharmacokinetic and pharmacodynamic advantages, and the structure is shown in formula (I):
WO2017186140 discloses a process for the preparation of compounds of formula (I).
The crystal structure of the compound used as a medicinal active ingredient often affects the chemical and physical stability of the medicament, and the difference of crystallization conditions and storage conditions can cause the change of the crystal structure of the compound and is sometimes accompanied by the generation of other forms of crystal forms. Therefore, it is necessary to improve various properties of the above products, and intensive research is needed to find new crystal forms with high purity and good chemical stability.
Disclosure of Invention
The invention aims to provide a novel crystal form of a compound shown as a formula (I), which has good stability and can be better applied to clinic.
The invention provides a II crystal form of a compound shown as a formula (I), which is characterized in that: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 5.38, 5.81, 6.72, 8.31, 11.82, 12.47, 13.45, 15.77, 16.66 and 17.96.
In certain embodiments, the present invention provides a crystalline form II of the compound of formula (I) having an X-ray powder diffraction pattern having characteristic peaks at 2 Θ angles of 3.94, 5.38, 5.81, 6.72, 8.31, 9.83, 11.82, 12.47, 13.45, 15.77, 16.66, 17.96, 18.89, 19.66, 20.83, 22.19, 23.23, 28.11, 29.62, and 34.38.
In certain embodiments, the present invention provides a crystalline form II of a compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in figure 3.
The present invention further provides a process for preparing crystalline form II of the compound of formula (I), said process comprising: mixing the compound shown in the formula (I) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent can be ethyl acetate.
The reaction temperature for the beating may be-20 ℃ to 200 ℃, for example, may be 0 ℃ to 100 ℃, preferably 0 ℃ to 30 ℃.
In another aspect, the present invention provides a crystal form III of a compound represented by formula (I), wherein: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 4.10, 5.97, 8.41, 11.17, 11.95, 15.95, 16.74, 17.46, 22.20 and 23.29.
In certain embodiments, the present invention provides a crystalline form III of a compound of formula (I), characterized in that: the X-ray powder diffraction pattern is shown in FIG. 5.
The present invention further provides a process for preparing crystalline form III of a compound of formula (I), said process comprising: mixing the compound shown in the formula (I) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent can be tetrahydrofuran.
The reaction temperature for the beating may be-20 ℃ to 200 ℃, for example, may be 0 ℃ to 100 ℃, preferably 0 ℃ to 30 ℃.
In another aspect, the present invention provides a crystalline form IV of a compound of formula (I), characterized in that: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 5.69, 7.84, 8.11, 10.93, 11.69, 15.61, 16.28, 17.15 and 17.55.
In certain embodiments, the present invention provides a crystalline form IV of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic peaks at angles 2 Θ of 3.90, 5.69, 7.84, 8.11, 10.93, 11.69, 15.61, 16.28, 17.15, 17.55, 21.75, and 22.02.
In certain embodiments, the present invention provides a crystalline form IV of the compound of formula (I) having an X-ray powder diffraction pattern having characteristic peaks at 2 Θ angles of 3.90, 5.69, 7.84, 8.11, 10.93, 11.69, 13.20, 14.57, 15.61, 16.28, 17.15, 17.55, 18.58, 19.53, 21.02, 21.75, 22.02, 22.77, 23.50, 23.95, 25.02, 25.63, 26.40, 27.36, 29.40, 30.20, 31.08, 33.08, 33.85, and 34.24.
In certain embodiments, the present invention provides a crystalline form IV of a compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in FIG. 7.
The present invention further provides a process for preparing form IV of a compound of formula (I), the process comprising: mixing the compound shown in the formula (I) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent can be DMF and/or DMAc.
The reaction temperature for the beating may be-20 ℃ to 200 ℃, preferably 0 ℃ to 100 ℃.
In another aspect, the present invention provides a crystalline form V of a compound of formula (I), characterized in that: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 5.73, 8.06, 11.69, 15.63, 16.19, 17.18, 21.80 and 22.08.
In certain embodiments, the present invention provides a crystalline form V of the compound of formula (I) having an X-ray powder diffraction pattern having characteristic peaks at 2 Θ angles of 3.91, 5.73, 8.06, 10.86, 11.69, 14.59, 15.63, 16.19, 17.18, 18.55, 19.61, 21.80, 22.08, 23.85, 26.58, 28.90, 30.14, 33.08, and 33.75.
In certain embodiments, the present invention provides a crystalline form V of a compound of formula (I) characterized by: the X-ray powder diffraction pattern is shown in FIG. 9.
The present invention further provides a process for preparing crystalline form V of a compound of formula (I), said process comprising: mixing the compound shown in the formula (I) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent can be one or more of ethyl acetate, isopropyl acetate and 1, 4-dioxane.
The reaction temperature for the beating may be-20 ℃ to 200 ℃, for example, may be 0 ℃ to 100 ℃, preferably 35 ℃ to 80 ℃.
The invention further relates to a pharmaceutical composition, which comprises one or more of crystal form II, crystal form III, crystal form IV and crystal form V of the compound shown in the formula (I), and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a pharmaceutical composition, which is prepared by mixing one or more of crystal form II, crystal form III, crystal form IV and crystal form V of the compound shown in the formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a preparation method of a pharmaceutical composition containing the compound shown in the formula (I) or pharmaceutically acceptable salts thereof, which comprises the step of mixing one or more of the II crystal form, the III crystal form, the IV crystal form and the V crystal form of the compound shown in the formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.
The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, the crystalline form or pharmaceutical preparation of the present invention may be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.
The invention further relates to the use of one or more of crystal form II, crystal form III, crystal form IV, crystal form V of the compound of formula (I) or the pharmaceutical composition of the invention for the preparation of a medicament for the treatment and/or prevention of a disease or disorder associated with a protein kinase, wherein the protein kinase is selected from the group consisting of EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase, preferably a cancer, preferably lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.
The crystal form obtained by the invention is subjected to structure determination and crystal form research through X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The crystallization method of the crystal form in the invention is conventional, such as volatile crystallization, cooling crystallization or room temperature crystallization.
The starting materials used in the preparation method of the crystal form of the invention can be compounds represented by formula (I) in any form, and specific forms include but are not limited to: amorphous, random crystalline, hydrate, solvate, and the like.
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The 'pulping' of the invention refers to a method for purifying by utilizing the characteristic that a substance has poor solubility in a solvent but impurities have good solubility in the solvent, and the pulping purification can remove color, change crystal forms or remove a small amount of impurities.
The "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern obtained by dividing the X-ray beam according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-ray,
the order n of diffraction is any positive integer, a first-order diffraction peak is generally taken, n is 1, when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The "X-ray powder diffraction pattern or XRPD" described herein is a pattern obtained by irradiation with Cu-K α in an X-ray powder diffractometer.
The differential scanning calorimetry or DSC in the invention refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance in the process of heating or keeping constant temperature of the sample so as to represent all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.
The 2 theta or 2 theta angle refers to a diffraction angle, theta is a Bragg angle and has the unit of DEG or degree, and the error range of 2 theta is +/-0.3 or +/-0.2 or +/-0.1.
The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
Advantageous effects of the invention
The compound shown in the formula (I) has high purity of crystal forms II, III, IV and V, good stability under the conditions of illumination, high temperature and high humidity, little change of HPLC purity, high chemical stability and almost no hygroscopicity, and is more beneficial to the drug action. The novel crystal form of the compound shown in the formula (I) can meet the medicinal requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be suitable for industrial production.
Drawings
FIG. 1 is an XRPD pattern for crystalline form I of a compound of formula (I);
FIG. 2 is a DSC of crystalline form I of the compound of formula (I);
FIG. 3 is an XRPD pattern for form II of the compound of formula (I);
FIG. 4 is a DSC of crystal form II of the compound of formula (I);
FIG. 5 is an XRPD pattern for the form III crystal form of the compound of formula (I);
FIG. 6 is a DSC of crystalline form III of the compound of formula (I);
FIG. 7 is an XRPD pattern for form IV of the compound of formula (I);
FIG. 8 is a DSC of form IV of the compound of formula (I);
FIG. 9 is an XRPD pattern for crystalline form V of the compound of formula (I);
FIG. 10 is a DSC of form V of the compound of formula (I);
FIG. 11 is an XRPD pattern for the crystalline form VI of the compound of formula (I);
FIG. 12 is a DSC chart of the crystalline form VI of the compound of formula (I);
figure 13 is a DVS profile of a crystalline form I of the compound represented by formula (I).
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the test:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: mettler Toledo DSC 1STAReSystem
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 40-250 deg.C
2. X-ray Diffraction Spectroscopy (XRPD)
The instrument model is as follows: BRUKER D8X-ray powder diffractometer
Monochromatic Cu-K α radiation (λ 1.5406)
The scanning mode is as follows: θ/2 θ, scan range: 2-40 °
Voltage: 40KV, current: 40mA
3. DVS dynamic moisture adsorption
The instrument model is as follows: SMS DVS Advantage
Temperature: 25 ℃;
solvent: water (W)
Humidity change: 50% -95% -0% -95% -50% RH, dm/dt is not more than 0.02%;
example 1
According to the method of example 3 of WO2017186140, the compound of formula (I) is obtained by recrystallization from an ethanol/acetone/water system. The X-ray diffraction pattern is shown in figure 1, the DSC pattern is shown in figure 2, and the characteristic peak positions are shown in the following table:
example 2
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding 2ml of isopropyl acetate, pulping at room temperature, performing suction filtration, and drying at 40 ℃ to obtain the I crystal form of the compound shown in the formula (I).
Example 3
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding 2ml of acetonitrile, pulping at room temperature, performing suction filtration, and drying at 40 ℃ to obtain the I crystal form of the compound shown in the formula (I).
Example 4
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding 2ml of dichloromethane, pulping at room temperature, performing suction filtration, and drying at 40 ℃ to obtain the I crystal form of the compound shown in the formula (I).
Example 5
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding 2ml of isopropyl ether, pulping at room temperature, filtering, and drying at 40 ℃ to obtain the I crystal form of the compound shown in the formula (I).
Example 6
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding DMSO2ml, pulping at room temperature, performing suction filtration, and drying at 40 ℃ to obtain the I crystal form of the compound shown in the formula (I).
Example 7
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding 2ml of water, pulping at room temperature, performing suction filtration, and drying at 40 ℃ to obtain the I crystal form of the compound shown in the formula (I).
Example 8
Putting 50g of the crystal form I of the compound shown in the formula (I) into a reaction bottle, adding 2ml of ethyl acetate, pulping at room temperature, performing suction filtration, and drying at 40 ℃ to obtain the crystal form II of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 3, the DSC pattern is shown in figure 4, and the characteristic peak positions are shown in the following table:
example 9
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding 2ml of tetrahydrofuran, pulping at room temperature, performing suction filtration, and drying at 40 ℃ to obtain the III crystal form of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 5, the DSC pattern is shown in figure 6, and the characteristic peak positions are shown in the following table:
example 10
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding DMF2ml, pulping at room temperature, performing suction filtration, and drying at 40 ℃ to obtain the IV crystal form of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 7, the DSC pattern is shown in figure 8, and the characteristic peak positions are shown in the following table:
example 11
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding 3ml of DMAc, pulping at 50 ℃, performing suction filtration, and drying at 40 ℃ to obtain the IV crystal form of the compound shown in the formula (I).
Example 12
Putting 50mg of the I crystal form of the compound shown in the formula (I) into a reaction bottle, adding 3ml of 1.4-dioxane, pulping at 50 ℃, filtering, and drying at 40 ℃ to obtain the V crystal form of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 9, the DSC pattern is shown in figure 10, and the characteristic peak positions are shown in the following table:
example 13
The compound of formula (I) was purified by column chromatography using dichloromethane/methanol as eluent according to WO2017186140, example 2, and concentrated to give the compound of formula (I) as crystalline form VI. The X-ray diffraction pattern is shown in figure 11, the DSC pattern is shown in figure 12, and the characteristic peak positions are shown in the following table:
example 14
Stability studies were performed on each of the crystalline forms of the compound of formula (I). The purity of the crystal form is detected by an Agilent 1200DAD high performance liquid chromatography system, a detection chromatographic column of the crystal form is Waters symmetry C18, (250 x 4.6mm,5 mu m), and a mobile phase: sodium dihydrogen phosphate/ACN/H2O, detection wavelength: 261 nm.
As can be seen from the table, each crystal form has good physical and chemical stability after long-term storage.
Claims (17)
1. A crystal form II of a compound shown as a formula (I) has an X-ray powder diffraction pattern which has characteristic peaks at 2 theta angles of 5.38, 5.81, 6.72, 8.31, 11.82, 12.47, 13.45, 15.77, 16.66 and 17.96,
2. the crystalline form II of the compound of formula (I) according to claim 1, characterized by the X-ray powder diffraction pattern shown in figure 3.
3. A crystal form III of a compound shown as a formula (I) has an X-ray powder diffraction pattern which has characteristic peaks at 2 theta angles of 4.10, 5.97, 8.41, 11.17, 11.95, 15.95, 16.74, 17.46, 22.20 and 23.29,
4. the crystalline form III of the compound of formula (I) according to claim 3, characterized by an X-ray powder diffraction pattern as shown in figure 5.
5. A compound of formula (I) in crystal form IV, which has an X-ray powder diffraction pattern with characteristic peaks at 2 theta angles of 5.69, 7.84, 8.11, 10.93, 11.69, 15.61, 16.28, 17.15 and 17.55,
6. the crystalline form IV of the compound of formula (I) according to claim 5, characterized by the X-ray powder diffraction pattern as shown in figure 7.
7. A crystal form V of a compound shown as a formula (I) has characteristic peaks at 2 theta angles of 5.73, 8.06, 11.69, 15.63, 16.19, 17.18, 21.80 and 22.08 in an X-ray powder diffraction pattern,
8. the crystalline form V of the compound of formula (I) according to claim 7, characterized by the X-ray powder diffraction pattern as shown in figure 9.
9. A crystalline form of the compound of formula (I) according to any one of claims 1 to 8, characterized in that: the error range of the 2 theta angle is +/-0.2.
10. A pharmaceutical composition prepared by mixing one or more of crystal form II, crystal form III, crystal form IV, and crystal form V of the compound of formula (I) according to any one of claims 1 to 9 with one or more pharmaceutically acceptable carriers, diluents, or excipients.
11. A pharmaceutical composition comprising one or more of form II, form III, form IV, form V of the compound of formula (I) according to any one of claims 1 to 9, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
12. A process for preparing a crystalline form II of the compound of formula (I) as claimed in any one of claims 1-2, which process comprises: mixing a compound shown as a formula (I) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent is selected from ethyl acetate, and the preferable reaction temperature of the pulping is 0-30 ℃.
13. A process for preparing the crystalline form III of the compound of formula (I) as claimed in claim 3 or 4, which process comprises: mixing a compound shown as a formula (I) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent is selected from tetrahydrofuran, and the preferable reaction temperature of the pulping is 0-30 ℃.
14. A process for preparing a crystalline form IV of a compound of formula (I) as claimed in any one of claims 5 to 6, which process comprises: mixing the compound shown in the formula (I) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent is selected from DMF and/or DMAc.
15. A process for preparing the crystalline form V of the compound of formula (I) as claimed in any one of claims 7 to 8, which process comprises: mixing the compound shown in the formula (I) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent is one or more selected from ethyl acetate, isopropyl acetate and 1, 4-dioxane, and the preferable reaction temperature of the pulping is 35-80 ℃.
16. A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises mixing one or more of form II, form III, form IV or form V of a compound of formula (I) as defined in any one of claims 1 to 9 with one or more pharmaceutically acceptable carriers, diluents or excipients.
17. Use of a crystalline form of a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 11 for the preparation of a medicament for the treatment and/or prevention of a disease or disorder associated with a protein kinase selected from EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase, preferably a cancer, preferably lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.
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| CN2018113076882 | 2018-11-05 | ||
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013131424A1 (en) * | 2012-03-09 | 2013-09-12 | 上海恒瑞医药有限公司 | 4-quinazoline amine derivative and application thereof |
| 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 |
| WO2017186140A1 (en) * | 2016-04-28 | 2017-11-02 | 江苏恒瑞医药股份有限公司 | Method for preparing tyrosine kinase inhibitor and derivative thereof |
| CN108314639A (en) * | 2018-05-09 | 2018-07-24 | 山东铂源药业有限公司 | Compound（E）-3-（1- methylpyrrolidin- 2- bases）Acrylic acid hydrochloride and synthetic method |
-
2019
- 2019-11-04 CN CN201911064120.7A patent/CN111138414A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013131424A1 (en) * | 2012-03-09 | 2013-09-12 | 上海恒瑞医药有限公司 | 4-quinazoline amine derivative and application thereof |
| 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 |
| WO2017186140A1 (en) * | 2016-04-28 | 2017-11-02 | 江苏恒瑞医药股份有限公司 | Method for preparing tyrosine kinase inhibitor and derivative thereof |
| CN108314639A (en) * | 2018-05-09 | 2018-07-24 | 山东铂源药业有限公司 | Compound（E）-3-（1- methylpyrrolidin- 2- bases）Acrylic acid hydrochloride and synthetic method |
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Application publication date: 20200512 |