CN115141177A - 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
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- CN115141177A CN115141177A CN202211050732.2A CN202211050732A CN115141177A CN 115141177 A CN115141177 A CN 115141177A CN 202211050732 A CN202211050732 A CN 202211050732A CN 115141177 A CN115141177 A CN 115141177A
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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 use in 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 novel 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 new 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 a 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 as 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-methylpyridine-3-yl) methoxy) pyridine-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile free alkali 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 the attached 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) pyridine-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 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, 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 in vacuum at 50 ℃ 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
FIG. 1 is an XRPD pattern for 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 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 following figures and specific examples so that those skilled in the art may better understand the present invention and practice it, but the examples are not intended to limit 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
1. 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 0.2 s. The light pipe voltage and current were 40 kV and 40 mA, 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)
Purity and solubility in the test were measured by Agilent 1260 HPLC, and the analytical conditions were as follows.
Chromatographic conditions are as follows:
a chromatographic column: ZORBAX Eclipse XDB-C18,4.6 mm 150 mm,5-Micron
Mobile phase: phase A: 0.1 mol/L sodium acetate aqueous solution (acetic acid adjusted pH = 5. + -. 0.5)
Phase B: acetonitrile
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: 1.0 mL/min
Column temperature: 30 deg.C
Temperature of the sample pan: 4 deg.C
Sample introduction volume: 10. mu.L of
Diluent agent: acetonitrile
Detection wavelength: 254 nm (length)
2. Preparation example
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 30 mg of the free base compound (API) prepared in example 1 was weighed in, 600 μ L of Dichloromethane (DCM) was added, and the appropriate amount of maleic acid ligand was weighed in at 0 ℃, with a molar ratio of API to ligand of 1.2. Reacting at 50 ℃ for 16 h 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
1 g of the free base compound (API) prepared in example 1 was weighed out, 8 mL of Tetrahydrofuran (THF) was added, 291.62 mg (1.2 eq) of maleic acid was weighed out and dissolved in 12 mL of THF, the THF solution of maleic acid was added dropwise to the API solution in ice bath, stirred at room temperature for 1 h, reacted at 50 ℃ for 16 h, then cooled to room temperature, filtered, and dried at 50 ℃ under vacuum for 20 h. 1.1 g of maleate 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 the 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, 1.5 mL of 2-methyltetrahydrofuran (2-MeTHF) was added, then 1.2eq (28.86 mg) of maleic acid was weighed out in 0.5 mL 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 ℃ and, after the addition was complete, stirred at room temperature for 3 h and then at 50 ℃ for 16 h. 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 20 h. 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 1 g of the free base compound (API) prepared in example 1, adding 7 mL of ethanol, weighing 288.9 mg (1.2 eq) of fumaric acid, dissolving in 13 mL of ethanol, dropwise adding the ethanol solution of fumaric acid into the ethanol solution of API under ice bath, stirring at room temperature for 1 h, reacting at 50 ℃ for 16 h, cooling to room temperature, filtering, and vacuum-drying at 50 ℃ for 20 h to obtain 1.08 g of fumaric acid crystal form A with the yield of 87%.
The XRPD pattern of form a fumarate 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 80% humidity, with a slight hygroscopicity.
Example 6: preparation of glycolate form a
1 g of the free base compound (API) from example 1 was weighed out and dissolved in Dichloromethane (DCM), 189.13 mg of glycolic acid was weighed out and dissolved in DCM and then added dropwise to the DCM solution of the API, after stirring for 1 h at room temperature, reaction was carried out for 16 h at 50 ℃ and then cooled to room temperature, filtration was carried out and vacuum drying was carried out for 20 h at 50 ℃ to obtain 710 mg 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, 2 ml of each 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) was added to each of the sample bottles, and the mixture was stirred 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. A suitable amount of sample was taken and then added with 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 lauryl sulfate and vitamin E polyethylene glycol succinate (5% TPGS), up to 8 ml, respectively, 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 are as follows: 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 in table 3 show that, upon standing at 25 ℃/60% rh for 4 weeks, free base form a degraded 0.02%, maleate form B degraded 0.01%, fumarate form a degraded 0.15%, glycolate form a degraded 0.02%. The results indicate that maleate form B is the most stable.
Competition in suspension experiment
To determine the most stable form of maleate, form a and form B of maleate were subjected to a suspension competition experiment. 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 test results for maleate form A and 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 (10)
- Crystalline maleate form a 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 7.7, 12.5, 13.6, 14.5, 16.8, 26.3 in the powder X-ray diffraction pattern of said form a.
- 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 in that it has a powder X-ray diffraction pattern with characteristic peaks at 2 Θ values of 7.7, 12.5, 13.6, 14.5, 16.8, 21.0, 23.1, 24.8, 26.3.
- 3. Crystalline maleate salt form a 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 4.
- 4. A process for preparing crystalline form a 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 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.
- 5. The preparation method according to claim 4, wherein 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.
- 6.6 crystalline maleate form B of- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile 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, 21.4, 24.9.
- 7. Crystalline maleate salt of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile according to claim 6, characterized in that it has a powder X-ray diffraction pattern with characteristic peaks in the 2 θ values of 7.8, 11.8, 13.5, 15.7, 17.2, 21.4, 23.7, 24.1, 24.9.
- 8. The crystalline maleate salt form B of 6- ((5-methoxy-6- ((6-methylpyridin-3-yl) methoxy) pyridin-3-yl) amino) -3-morpholinoquinoxaline-5-carbonitrile according to claim 6 having a powder X-ray diffraction pattern as shown in figure 6.
- 9. The process for the preparation of crystalline 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 6 to 8, 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.
- 10. Process for the preparation of 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 6 to 8 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 in vacuum at 50 ℃ to obtain the crystal form B.
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