CN115141177B - Novel crystal form of quinoxaline compound maleate and preparation method thereof - Google Patents
Novel crystal form of quinoxaline compound maleate and preparation method thereof Download PDFInfo
- Publication number
- CN115141177B CN115141177B CN202211050732.2A CN202211050732A CN115141177B CN 115141177 B CN115141177 B CN 115141177B CN 202211050732 A CN202211050732 A CN 202211050732A CN 115141177 B CN115141177 B CN 115141177B
- Authority
- CN
- China
- Prior art keywords
- methoxy
- maleate
- crystal form
- morpholinoquinoxaline
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel crystal form of quinoxaline compound maleate and a preparation method thereof. Compared with free alkali of quinoxaline compound, fumarate crystal form A and glycolate crystal form A, the novel crystal form of maleate of quinoxaline compound has better solubility and higher stability under certain conditions.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a novel crystal form of a quinoxaline compound maleate and a preparation method thereof.
Background
Receptor Tyrosine Kinases (RTKs) are multimotif transmembrane proteins that act on receptors for cytokines, growth factors, hormones, and other signaling molecules. Receptor tyrosine kinases are a large part of the branching of the protein tyrosine kinase family. Studies have shown that receptor tyrosine kinases play an important role in a variety of cellular processes, including growth, differentiation, angiogenesis, and the progression of a variety of cancers. Inhibition of receptor tyrosine kinases appears to be an effective measure in the treatment of cancer. There are over 20 small molecule kinase inhibitors approved by the FDA for various cancer treatments, and a large number of kinase inhibitors are currently in various stages of clinical trials. WO2018071348A1 discloses a quinoxaline compound as a type III receptor tyrosine kinase inhibitor and a preparation method thereof, however, the patent document does not disclose a crystal form and a preparation method of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile maleate.
The research and development of crystals are very important in the research and development of medicines, the compounds with different crystal forms have different bioavailability and solubility, and the crystal forms have great influence on the stability, processability, bioavailability, solubility, preparation, industrial production and transportation and the like of the compounds, so that the development of the stable crystal form of the proper salt of the 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile (the compound shown in the formula I) has great significance for the medicine research.
Disclosure of Invention
The invention aims to solve the technical problem of providing a new maleate crystal form of a quinoxaline compound and a preparation method thereof. Specifically, the invention provides a maleate crystal form A and a maleate crystal form B of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile and a preparation method thereof.
In order to solve the technical problems, the invention provides the following technical scheme:
in a first aspect, the present invention provides a novel crystalline form of the maleate salt of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile, defined as form a, having characteristic peaks in its powder X-ray diffraction pattern at 2 Θ values of 7.7, 12.5, 13.6, 14.5, 16.8, 26.3.
Further, in the powder X-ray diffraction pattern of the crystal form A, characteristic peaks exist at 2 theta values of 7.7, 12.5, 13.6, 14.5, 16.8, 21.0, 23.1, 24.8 and 26.3.
Further, the powder X-ray diffraction pattern of the crystal form A is shown in the attached figure 4.
Further, the invention provides a preparation method of the maleate crystal form A of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile, which comprises the following steps:
dissolving 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile free base in a solvent, adding a maleic acid ligand at 0 ℃, reacting at 25-50 ℃ under the condition of stirring, cooling to room temperature after the reaction is finished, filtering, continuously cooling the filtrate to 0 ℃, and filtering to obtain the crystal form A.
In the present invention, "room temperature" is defined as a temperature range of 5 to 35 ℃ such as 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ and the like.
Further, the molar ratio of the free base to the maleic acid ligand is 1.2, and the solvent is selected from one or more of tetrahydrofuran, dichloromethane, ethanol and acetone.
In a second aspect, the present invention provides another novel crystalline form of the maleate salt of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile, defined as form B, having a powder X-ray diffraction pattern with characteristic peaks at 2 Θ values of 7.8, 11.8, 13.5, 15.7, 21.4, 24.9.
Further, in the powder X-ray diffraction pattern of the crystal form B, characteristic peaks exist at 2 theta values of 7.8, 11.8, 13.5, 15.7, 17.2, 21.4, 23.7, 24.1 and 24.9.
Further, the powder X-ray diffraction pattern of the crystal form B is shown in figure 6.
Further, the invention provides a preparation method of the maleate crystal form B of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile, which comprises the following steps:
dissolving 6- ((5-methoxy-6- ((6-methylpyridine-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile free base in tetrahydrofuran, dropwise adding a tetrahydrofuran solution of maleic acid under ice bath, stirring, and reacting at 50 ℃; and after the reaction is finished, cooling to room temperature, filtering, and then carrying out vacuum drying at 50 ℃ to obtain the crystal form B.
Further, the invention also provides another preparation method, which comprises the following steps:
dissolving 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile free base in 2-methyltetrahydrofuran, adding a 2-methyltetrahydrofuran solution of maleic acid dropwise at-15 deg.C, stirring, and reacting at 50 deg.C; and after the reaction is finished, cooling to room temperature, filtering, leaching by using cold 2-methyltetrahydrofuran, and drying a filter cake at 50 ℃ in vacuum to obtain the crystal form B.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides two new maleate crystal forms of 6- ((5-methoxy-6- ((6-methylpyridine-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile, namely a crystal form A and a crystal form B, and compared with free alkali, a fumarate crystal form A and a glycolate crystal form A, the two new maleate crystal forms have better solubility and higher stability under certain conditions.
Drawings
Figure 1 is an XRPD pattern of the free base;
FIG. 2 is a TGA/DSC stackup of the free base;
FIG. 3 is a PLM profile of the free base;
figure 4 is an XRPD pattern of maleate form a;
figure 5 is a TGA/DSC overlay of maleate form a;
FIG. 6 is an XPRD spectrum of maleate form B;
FIG. 7 is a TGA/DSC overlay of maleate form B;
figure 8 is a DVS curve for maleate form B;
figure 9 is an XRPD overlay before and after DVS testing of a maleate form B sample;
figure 10 is an XRPD spectrum of fumarate salt form a;
figure 11 is a TGA/DSC profile of form a of the fumarate salt;
figure 12 is a DVS profile of fumarate form a;
figure 13 is an XRPD spectrum of glycolate form a;
FIG. 14 is a TGA/DSC spectrum of crystalline form A of the glycolate;
figure 15 is a DVS curve for glycolate form a.
Detailed Description
The present invention is further described below in conjunction with the drawings and the embodiments so that those skilled in the art can better understand the present invention and can carry out the present invention, but the embodiments are not to be construed as limiting the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
1. Analytical test method
X-ray powder diffractometer (XRPD)
And carrying out crystal form analysis on the sample by using an X-powder diffractometer. The 2 theta scan angle of the sample was 3 deg. to 42 deg., the scan step size was 0.02 deg., and the scan time per step was 0.2s. The light pipe voltage and current were 40kV and 40mA, respectively. During sample preparation, a proper amount of sample is placed on a sample carrying disc, and is pressed flat by a spoon, a glass sheet or other tools, so that the surface of the sample is ensured to be smooth and flat.
2. Differential Scanning Calorimetry (DSC)
Samples were analyzed using a TA Instruments Discovery DSC 25. The weighed sample was placed in a loading tray and the sample was raised to the final temperature at a rate of 10 deg.C/min under nitrogen (50 ml/min).
3. Thermogravimetric analyzer (TGA)
Samples were analyzed using TA Instruments TGA Discovery 550. The samples were placed in tared aluminum pans, the system was automatically weighed, and the samples were then raised to the final temperature at a rate of 10 ℃/min under nitrogen.
4. High Performance Liquid Chromatography (HPLC)
The purity and solubility in the test were determined by Agilent 1260 high performance liquid chromatography under the following analytical conditions.
Chromatographic conditions are as follows:
and (3) chromatographic column: ZORBAX Eclipse XDB-C18,4.6mm 150mm,5-Micron
Mobile phase: phase A: 0.1mol/L sodium acetate aqueous solution (acetic acid adjusted pH = 5. + -. 0.5)
Phase B: acetonitrile (ACN)
Elution procedure:
time (min) | 0.0 | 9.0 | 15.0 | 20.0 | 25.0 | 26.0 | 30.0 |
B(%) | 30.0 | 45.0 | 45.0 | 90.0 | 90.0 | 30.0 | 30.0 |
Flow rate: 1.0mL/min
Column temperature: 30 deg.C
Temperature of sample pan: 4 deg.C
Sample introduction volume: 10 μ L
Diluent agent: acetonitrile
Detection wavelength: 254nm
2. Preparation examples
Example 1: preparation of free base crystalline form a
The 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile free base compound (free base form a) was prepared according to the method disclosed in WO2018071348A1 and has the XRPD pattern shown in fig. 1, the TGA/DSC pattern shown in fig. 2, and the polarization microscope (PLM) pattern shown in fig. 3.
Example 2: preparation of maleate form a
About 30mg of the free base compound (API) from example 1 was weighed out, 600. Mu.L of Dichloromethane (DCM) was added, and the appropriate amount of maleic ligand was weighed out at 0 ℃ and added in a molar ratio of API to ligand of 1.2. Reacting at 50 ℃ for 16h under the action of magnetic stirring, then cooling to room temperature, filtering, and continuously cooling the filtrate to 0 ℃ and then filtering. The solid sample was then analyzed to obtain maleate form a.
The XRPD pattern of crystalline maleate form a prepared is shown in figure 4, and the TGA/DSC overlay is shown in figure 5.
Example 3: preparation of maleate form B
1g of the free base compound (API) prepared in example 1 was weighed out, 8mL of Tetrahydrofuran (THF) was added, 291.62mg (1.2 eq) of maleic acid was weighed out and dissolved in 12mL of THF, the THF solution of maleic acid was added dropwise to the API solution in ice bath, stirred at room temperature for 1h, reacted at 50 ℃ for 16h, then cooled to room temperature, filtered, and dried at 50 ℃ under vacuum for 20h. 1.1g of the maleate salt was obtained in 88.9% yield. XRPD showed that the maleate salt was not identical to the maleate salt form a prepared in example 2, designated as maleate salt form B.
Figure 6 shows an XRPD pattern of maleate form B. Figure 7 shows a TGA/DSC profile of maleate form B. Figure 8 is a DVS curve of maleate form B showing 0.1784% weight gain with little hygroscopicity at 80% humidity. Figure 9 shows XRPD overlay before and after DVS testing of samples of maleate form B showing no change in form before and after DVS testing.
Example 4: preparation of maleate form B
About 100mg of the free base compound (API) prepared in example 1 was weighed out, 1.5mL of 2-methyltetrahydrofuran (2-MeTHF) was added, then 1.2eq (28.86 mg) of maleic acid was weighed out in 0.5mL of 2-MeTHF, and the solution of maleic acid in 2-MeTHF was added dropwise to the suspension of API in 2-MeTHF at-15 deg.C, after the addition was complete, stirring was carried out at room temperature for 3h, then at 50 deg.C for 16h. The temperature is reduced to room temperature and filtered, the cold 2-MeTHF is rinsed twice, and the filter cake is dried in vacuum at 50 ℃ for 20h. About 100mg of a pale yellow solid was obtained. The crystal form is the same as the maleate crystal form B.
Example 5: preparation of fumarate salt form A
Weighing 1g of the free base compound (API) prepared in example 1, adding 7mL of ethanol, weighing 288.9mg (1.2 eq) of fumaric acid, dissolving in 13mL of ethanol, dropwise adding the ethanol solution of fumaric acid into the ethanol solution of API under ice bath, stirring at room temperature for 1h, reacting at 50 ℃ for 16h, cooling to room temperature, filtering, and vacuum-drying at 50 ℃ for 20h to obtain 1.08g of fumaric acid crystal form A with the yield of 87%.
The XRPD pattern of fumaric acid form A is shown in figure 10. Figure 11 shows a TGA/DSC profile of fumarate salt form a. The DVS curve is shown in fig. 12, which shows a weight gain of 0.4332% at a humidity of 80%, and a slight hygroscopicity.
Example 6: preparation of glycolate form a
1g of the free base compound (API) from example 1 was weighed out and dissolved in Dichloromethane (DCM), 189.13mg of glycolic acid was weighed out and dissolved in DCM and then added dropwise to the DCM solution of the API, after stirring for 1h at room temperature, reaction was carried out for 16h at 50 ℃ and then cooled to room temperature, filtration and vacuum drying for 20h at 50 ℃ gave 710mg of glycolate form A.
The XRPD spectrum of glycolate form a is shown in fig. 13, and the TGA/DSC spectrum of glycolate form a is shown in fig. 14. The DVS curve is shown in fig. 15, and the results show a moisture pick-up of 0.3754% at a humidity of 80%, indicating a slight hygroscopicity.
3. Test example
1. Solubility comparison of different salt forms with free base Compounds
About 20 mg of the starting material (free base form a), the maleate form B prepared in example 4, the fumarate form a prepared in example 5 and the glycolate form a prepared in example 6 were weighed into sample bottles, and 2ml of FaSSIF, feSSIF, SGF, water and a buffer solution having a pH of 1.2 (potassium chloride), 3.0 (potassium hydrogen phthalate), 4.5 (sodium acetate trihydrate), 6.8 (potassium dihydrogen phosphate) and 7.5 (potassium dihydrogen phosphate) were added to each sample bottle, followed by stirring in a water bath at 37 ℃. Samples were taken at 2 and 24 hour time points, respectively. The filtrate was tested for HPLC and the remaining solid was tested for XRPD. The test results are shown in table 1.
Table 1 comparison of the solubility of different salt forms with the free base compound
As can be seen from the results in table 1, all samples have very little solubility in the rest of the buffers except SGF and the buffer with pH =1.2 (the solubility is greatest for maleate form B, and reaches 0.4007mg/mL in SGF).
In order to screen primarily the effect of the solubilizer on free base form a, maleate form B, fumarate form a and glycolate form a, the solubility of the samples was roughly tested by observation. Taking appropriate amount of sample, then adding different kinds of solubilizers-water, sulfobutyl-beta-cyclodextrin sodium (20% SBECD), hydroxypropyl-beta-cyclodextrin (20% HPCD), 20% PEG400, 5% Solutol HS15, 1% Tween-80, 1% sodium dodecyl sulfate and vitamin E polyethylene glycol succinate (5% TPGS), respectively, up to 8ml, the solubility results are shown in Table 2. Preliminary screening shows that the solubility of the maleate crystal form B in a 1% sodium dodecyl sulfate aqueous solution can reach more than 1 mg/mL.
TABLE 2 crude solubility of the samples in solubilizer
2. Stability evaluation
Putting a certain amount of samples (free base crystal form A, maleate crystal form B, fumarate crystal form A and glycolate crystal form A) into a stability test box, and taking out after a certain time to detect HPLC and XRPD. And (3) testing conditions: 25 ℃/60% rh (open), sampling time: one week, two weeks, four weeks. The results are shown in Table 3.
Table 3 stability test results for candidate crystalline forms
The stability results of table 3 show that upon standing at 25 ℃/60% rh for 4 weeks, free base form a was degraded 0.02%, maleate form B was degraded 0.01%, fumarate form a was degraded 0.15%, glycolate form a was degraded 0.02%. The results indicate that maleate form B is the most stable.
3. Competition in suspension experiment
To determine the most stable form of maleate, form a and form B of maleate were subjected to suspension competition experiments. The maleate crystal form A and the maleate crystal form B with the same mass are weighed and respectively added into different solvents, suspension competition pulping experiments are carried out at 50 ℃, the crystal forms are detected in 1 day and 3 days, and the results are shown in Table 4.
Table 4 suspension competition experiment results for maleate form a and form B
Numbering | Solvent(s) | 1 |
3 days |
1 | Acetic acid ethyl ester | Crystal form B | |
2 | Methylene dichloride | Form B, low crystallinity | Form B, |
3 | Acetone (II) | Crystal form A + crystal form B | Less peaks than form B |
4 | 2-methyltetrahydrofuran | Crystal form B | Crystal form B |
5 | Tetrahydrofuran (THF) | Form B, low crystallinity | Crystal form B |
6 | N-hexane | Crystal form A + crystal form B | Crystal form B |
7 | Water (W) | Crystal form A + crystal form B | Crystal form B |
As can be seen from the results in table 4, form a was transformed into form B in ethyl acetate, dichloromethane, 2-methyltetrahydrofuran, tetrahydrofuran for 1 day, and was completely transformed into form B in acetone, n-hexane, and water for 3 days, so that form B was more stable than form a in the above-mentioned solvent.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.
Claims (5)
- Crystalline maleate form B of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile, characterized in that characteristic peaks are present at 2 θ values of 7.8, 11.8, 13.5, 15.7, 21.4, 24.9 in the powder X-ray diffraction diagram of said form B.
- 2. Crystalline maleate salt of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile according to claim 1 characterized by the presence of characteristic peaks in the powder X-ray diffraction pattern of form B at 2 Θ values of 7.8, 11.8, 13.5, 15.7, 17.2, 21.4, 23.7, 24.1, 24.9.
- 3. Crystalline maleate form B of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile according to claim 1 having a powder X-ray diffraction pattern as shown in figure 6.
- 4. The process for the preparation of crystalline form B of the maleate salt of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile according to any of claims 1 to 3, comprising the steps of:dissolving 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile free base in tetrahydrofuran, dropwise adding a tetrahydrofuran solution of maleic acid under ice bath, stirring, and reacting at 50 ℃; and after the reaction is finished, cooling to room temperature, filtering, and then drying in vacuum at 50 ℃ to obtain the crystal form B.
- 5. A process for preparing the maleate form B of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile according to any of claims 1 to 3 comprising the steps of:dissolving 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile free base in 2-methyltetrahydrofuran, dropwise adding a 2-methyltetrahydrofuran solution of maleic acid at-15 ℃, stirring, and reacting at 50 ℃; and after the reaction is finished, cooling to room temperature, filtering, leaching by using cold 2-methyltetrahydrofuran, and drying a filter cake at 50 ℃ in vacuum to obtain the crystal form B.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211050732.2A CN115141177B (en) | 2022-08-30 | 2022-08-30 | Novel crystal form of quinoxaline compound maleate and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211050732.2A CN115141177B (en) | 2022-08-30 | 2022-08-30 | Novel crystal form of quinoxaline compound maleate and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115141177A CN115141177A (en) | 2022-10-04 |
CN115141177B true CN115141177B (en) | 2022-12-09 |
Family
ID=83416340
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211050732.2A Active CN115141177B (en) | 2022-08-30 | 2022-08-30 | Novel crystal form of quinoxaline compound maleate and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115141177B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018071348A1 (en) * | 2016-10-10 | 2018-04-19 | Development Center For Biotechnology | Quinoxaline compounds as type iii receptor tyrosine kinase inhibitors |
-
2022
- 2022-08-30 CN CN202211050732.2A patent/CN115141177B/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN115141177A (en) | 2022-10-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2833470C (en) | Processes for preparing form 1 zd1839 polymorph | |
JP2014221831A (en) | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide | |
EP4011867B1 (en) | Crystal forms c and e of pyrazin-2(1h)-one compound and preparation method therefor | |
CA2796192A1 (en) | Polymorphs of osi-906 | |
CN114174272B (en) | Preparation method of pyrazin-2 (1H) -ketone compound | |
CN105801476A (en) | Crystal form II of Apatinib mesylate as well as preparation method and application of crystal form II | |
EP3805229B1 (en) | Salt of fused ring pyrimidine compound, crystal form thereof and preparation method therefor and use thereof | |
WO2018059534A1 (en) | Crystal form and salt form of and preparation method for tyrosine kinase inhibitor | |
CN115141177B (en) | Novel crystal form of quinoxaline compound maleate and preparation method thereof | |
CN111479809A (en) | Crystal form and salt form of TGF- β RI inhibitor and preparation method thereof | |
CN114174270B (en) | Crystal forms A and B of pyrazine-2 (1H) -ketone compound and preparation method thereof | |
CN113906035B (en) | Synthesis method of furan imidazopyridines, crystal forms of furan imidazopyridines and crystal forms of salts thereof | |
CN111471048A (en) | Compound with nitrogen-containing bridged ring, spiro ring or fused ring structure and application thereof | |
CA3130247C (en) | Fgfr inhibitor compound in solid form and preparation method therefor | |
CN106928232A (en) | The crystal formation of quinolines and its salt, preparation method, composition and application | |
CN110078706B (en) | Imatinib derivative and preparation method and application thereof | |
WO2024109871A1 (en) | Pharmaceutically acceptable salt of nitrogen-containing heterocyclic compound, crystal form thereof, and preparation method therefor | |
WO2023130878A1 (en) | Glp-1 agonist salt, and crystal form and medical use thereof | |
CN105801505B (en) | A kind of method and application that 5- azauracils are prepared by oteracil potassium |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |