CN111303097B - Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof - Google Patents
Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof Download PDFInfo
- Publication number
- CN111303097B CN111303097B CN201811515329.6A CN201811515329A CN111303097B CN 111303097 B CN111303097 B CN 111303097B CN 201811515329 A CN201811515329 A CN 201811515329A CN 111303097 B CN111303097 B CN 111303097B
- Authority
- CN
- China
- Prior art keywords
- degrees
- dimethylamine
- fumarate
- michelia lactone
- crystal form
- 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
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a crystal form C of michelia lactone fumarate of dimethylamine and a preparation method thereof. The characteristic that the relative peak intensity of the X-ray powder diffraction 2 theta is 100 +/-0.2 degrees, 7.4 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.1 +/-0.2 degrees, 13.1 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 18.3 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.5 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.9 +/-0.2 degrees, 24.4 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.2 +/-0.2 degrees, 26.9 +/-0.2 degrees, 27.4 +/-0.2 degrees, 28.1 +/-0.2 degrees, 29.3 +/-0.2 degrees, 29.5 +/-0.2 degrees, 26.6 +/-0.2 degrees, 31.0.2 degrees, 31 +/-0.2 degrees, 31.5 +/-2 degrees, and 31.2 degrees is shown as the initial peak intensity of the peak intensity. The preparation process is constant-temperature suspension crystal transformation preparation, the process method is simple and easy to operate, the reproducibility is good, the purity of the obtained product is more than 99%, the yield is higher than 90%, the stability is good, the bulk density is high, the surface is smooth and clean, and the preparation process has complete rod-shaped crystal habit and is suitable for amplification production.
Description
Technical Field
The invention belongs to the technical field of medical crystallization, and particularly relates to a dimethylamine michelia lactone fumarate crystal form C and a preparation method thereof.
Background
Tumors, especially malignant tumors, have posed a serious health hazard to humans. At present, the cytotoxic anticancer drugs are widely applied clinically. The medicine is similar to a sword with one handle and two blades, has poor selectivity and strong toxic and side effects, and is easy to generate drug resistance. More and more scientific research has found that: cancer stem cells are the root cause of most cancers to develop, progress, relapse, drug resistance, and metastasis. The current clinical medication and radiotherapy means only aim at common cancer cells, but can not selectively kill cancer stem cells.
In recent years, the research and development of anticancer drugs has focused on finding compounds having anticancer activity from natural products. According to FDA statistics, more than three-fourths of the drugs on the market in the world are natural products or modified modifications thereof. A study reported in the journal of Nature, International academic publication, indicates that a sesquiterpene lactone compound, Parthenolide, extracted from feverfew has a selective killing effect on cancer stem cells. Parthenolide is a sesquiterpene lactone compound extracted from feverfew, and is unstable under acidic or alkaline conditions. In order to improve the stability of the derivative, the derivative is modified to obtain micheliolide, which is called Michelolide (MCL) in English and belongs to guaiane type sesquiterpene lactone compounds, and related documents and patents report that the micheliolide has the effect of treating cancer diseases, but the water solubility is poor. In order to improve water solubility and bioactivity, michelia lactone derivative, namely dimethylamine michelia lactone, with the molecular formula of C is obtained by heating reaction in methanol solvent with triethylamine as a catalyst 17 H 27 NO 3 The structural formula is shown in the specification, namely Dimethylaminomichalilide (DMAMCL), and the DMAMCL has a certain degree of improvement in water solubility compared with the MCL, but can be degraded and unstable after being placed for a long time. To further improve their water solubility and stability, they are usually prepared in the form of salts, hairIt has been found by the present inventors that the dimethylamine smilactone fumarate, derived from parthenolide, has the formula C 21 H 31 NO 7 The molecular weight 409 is white crystalline powder, is odorless, and is soluble in water, methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, and isopropyl acetate, and is almost insoluble in cyclohexane, n-hexane, n-heptane, dichloromethane, isopropyl ether, and toluene. The chemical structural formula is as follows:
patent CN103724307B discloses dimethylamine michelia lactone fumarate crystal form a and a preparation method thereof, and although the crystal form a has various advantages over the amorphous dimethylamine michelia lactone fumarate, the bulk density of the crystal form a is small, only reaches 0.270g/mL, the particle size is small, the main particle size is 35.8 μm, the coalescence is severe, the angle of repose is 62 degrees, the fluidity is poor, and the later-stage preparation of the finished medicine is not convenient. In addition, the crystal form A is easy to generate crystal form transformation in a solvent environment, storage and transportation are affected, and a plurality of problems are brought to later-stage processing and treatment.
In order to overcome the defects of the prior art and solve the problems that the current crystal form A product is easy to generate crystal form conversion, poor in stability, poor in fluidity, small in particle size, easy to agglomerate and the like, the influence of different crystallization modes, single solvents and mixed solvents, different temperatures and stirring conditions on the crystal form of the final product needs to be inspected by means of high-throughput crystal form sample screening, and a simple and controllable process technical route with good reproducibility, safety and low toxicity is developed by combining various analysis and test methods such as powder diffraction, single crystal diffraction, thermogravimetry analysis and differential scanning calorimetry analysis, so that a new crystal form product with excellent performance is prepared and found, and the subsequent drug development is facilitated.
Disclosure of Invention
The invention provides the dimethylamine michelia lactone fumarate crystal form C which has good stability, high purity, high yield, rod-shaped crystal habit, smooth surface, difficult coalescence and high bulk density and the preparation method thereof.
The invention provides a crystal form C of michelia lactone fumarate of dimethylamine, which is characterized in that an X-ray powder diffraction pattern obtained by using Cu-Kalpha ray measurement is shown in figure 1, and characteristic peaks are shown at 6.4 +/-0.2 degrees, 7.4 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.1 +/-0.2 degrees, 13.1 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 18.3 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 26.9 +/-0.2 degrees and 27.4 +/-0.2 degrees by a diffraction angle 2 theta, wherein the 6.4 +/-0.2 degrees is an initial peak, and the relative intensity of the characteristic peak at the 7.4 +/-0.2 degrees is 100 percent.
The crystal form C of the michelia lactone fumarate of dimethylamine is characterized in that the diffraction angle of an X-ray powder diffraction pattern obtained by using Cu-Kalpha ray measurement and expressed by a 2 theta angle also has characteristic peaks at 19.8 +/-0.2 degrees, 22.5 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.9 +/-0.2 degrees, 24.4 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.2 +/-0.2 degrees, 28.1 +/-0.2 degrees, 29.3 +/-0.2 degrees, 29.5 +/-0.2 degrees, 30.6 +/-0.2 degrees, 31.0 +/-0.2 degrees and 31.5 +/-0.2 degrees.
The invention provides a crystal form C of michelia lactone fumarate of dimethylamine, which is characterized in that the crystal form is a monoclinic system, the space group is P2(1), and the unit cell parameter is
α is 90 °, β is 114.15(3 °), γ is 90 °, and unit cell volume is
The crystal form C of the michelia lactone fumarate of dimethylamine provided by the invention is characterized in that differential scanning calorimetry analysis is shown in figure 2, a characteristic endothermic peak is shown at 155 +/-2 ℃ and is a melting peak, the thermal weight loss analysis of the crystal form is shown in figure 3, no weight loss exists before the melting temperature, the crystal form is a solvent-free compound,
the crystal form C of the michelia lactone fumarate dimethylamine can be prepared by a constant-temperature solvent mediated crystal transformation method: under the stirring action, adding the solid raw material of the michelia lactone fumarate into a solvent with a constant temperature of 35-50 ℃, wherein the mass ratio of the solid raw material of the michelia lactone fumarate to the solvent is 0.01-0.06:1, stirring for 24-48h, filtering and drying to obtain the crystal form C compound of the michelia lactone fumarate of dimethylamine.
The solvent is selected from any one of acetone, acetonitrile, tetrahydrofuran, 1, 4-dioxane and methyl isobutyl ketone.
The drying condition is that the drying is carried out for 6 to 10 hours at the temperature of between 30 and 40 ℃ and under the normal pressure condition.
A dimethylamine michelia lactone fumarate crystal form A product reported in the prior patent can be converted into a solvent-free compound crystal form C provided by the invention after suspension for 24 hours at room temperature or 50 ℃ in a plurality of single solvents such as acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, 1, 4-dioxane, methyl isobutyl ketone and the like. However, the crystal form C of the michelia lactone dimethylamine fumarate provided by the invention can not be subjected to crystal transformation after suspension for 1 week experiment in a plurality of single solvents such as acetone, acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl acetate, 1, 4-dioxane, methyl isobutyl ketone and the like at room temperature or high temperature of 50 ℃, and the product is still in the crystal form C. Therefore, compared with the crystal form A, the crystal form C is a crystal form with more stable thermodynamics, and the problem that the crystal form A reported in the patent is easy to generate crystal form transformation, so that the stability is poor and the post-processing is not facilitated is fundamentally solved.
The constant-temperature solvent-mediated crystal transformation preparation method of the crystal form C of the michelia lactone fumarate of dimethylamine provided by the invention has the advantages of simple process, easy preparation, good repeatability, product yield higher than 99% and purity higher than 90%.
The crystal habit of the crystal form C product of the michelia lactone fumarate dimethylamine is inspected, the obtained product is rod-shaped, the crystal habit is complete, the surface is smooth and clean, the coalescence phenomenon does not exist, and the scanning electron microscope image of the product is shown in an attached figure 4. An electron microscope scanning photo of a dimethylamine michelia lactone fumarate A crystal form product reported in the prior patent is shown as an attached figure 5, and the product is prepared by adopting a natural cooling recrystallization method, and has the advantages of small product granularity, main granularity of 35.8 mu m, serious coalescence phenomenon, bulk density of 0.270g/mL, angle of repose of 62 degrees and poor fluidity. Compared with a crystal form A product, the anhydrous crystal form C provided by the invention has the main particle size of 56.3 mu m, the bulk density of 0.477g/mL and the angle of repose of 46 degrees, improves the particle size to a certain extent, and solves the problems of small bulk density and poor fluidity.
According to the invention, the stability of the crystal form C of the michelia lactone fumarate of dimethylamine is inspected, the anhydrous crystal form compound product is uniformly distributed in an open culture dish, the temperature is controlled at 25 ℃, the humidity is 50%, the thickness of the sample is less than 5mm, the anhydrous crystal form compound product is hermetically placed in a drier for 30 days, then the samples placed for 7 days, 14 days and 30 days are respectively subjected to XRD detection, and the detection result is compared with the detection result of the day 0. The specific spectrum is shown in figure 6, and the result shows that the XRD spectrum is not obviously changed. Meanwhile, the purity of the samples which are placed for 7 days, 14 days and 30 days is respectively analyzed, and compared with the purity detection result of the sample at the 0 th day, the purity of the sample at the 7 th day is only changed by 0.02%, the purity of the sample at the 14 th day is only changed by 0.06%, the purity of the sample at the 30 th day is only changed by 0.14%, and the purity of the sample is not obviously changed. And the XRD pattern and the purity analysis result are combined, so that the dimethylamine michelia lactone fumarate crystal form C is proved to have good stability.
Drawings
FIG. 1 is an X-ray diffraction pattern of crystalline form C of michelia lactone fumarate of dimethylamine according to the invention.
Figure 2 is a differential scanning calorimetry thermogram of crystalline form C of michelia lactone fumarate of dimethylamine according to the invention.
FIG. 3 is a thermogravimetric analysis of crystalline form C of michelia lactone fumarate of dimethylamine of the present invention.
FIG. 4 is a scanning electron micrograph (300 times magnification) of crystalline form C of michelia lactone fumarate dimethylamine of the present invention.
FIG. 5 is a scanning electron microscope of a product of crystal form A prepared according to the method disclosed in patent CN103724307B
Graph (200 times magnification).
FIG. 6 is a comparison of stability test profiles of crystalline form C of michelia lactone fumarate of dimethylamine of the present invention, wherein
The XRD spectrograms of the samples which are placed for 0 day, 7 days, 14 days and 30 days are sequentially arranged from bottom to top.
Detailed Description
The foregoing and other aspects of the present invention will be apparent from, and elucidated with reference to, the embodiments described hereinafter, without being construed as limited by the scope of the subject matter of the invention set forth in the claims. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1
Putting 0.03g of raw material of michelia lactone dimethylamine fumarate into a 4mL sample bottle, adding 3g of acetone solvent to dissolve the raw material and keep the raw material in a supersaturated state, stirring the mixture at 35 ℃ to perform solvent-mediated crystal transformation, filtering the suspension after 24h to obtain a white solid, and drying the white solid at 30 ℃ under normal pressure for 6h to obtain the michelia lactone dimethylamine fumarate crystal. The X-ray powder diffraction pattern of the product has characteristic peaks expressed by 2 theta at 6.4 degrees, 7.4 degrees, 11.6 degrees, 12.1 degrees, 13.1 degrees, 14.5 degrees, 15.1 degrees, 15.5 degrees, 15.9 degrees, 18.3 degrees, 18.6 degrees, 19.3 degrees, 20.5 degrees, 22.0 degrees, 26.9 degrees and 27.4 degrees, wherein 6.4 degrees is an initial peak, the relative intensity of the characteristic peaks at 7.4 degrees is 100 percent, and in addition, the diffraction angles expressed by 2 theta angles of the X-ray powder diffraction pattern of the product also have characteristic peaks at 19.8 degrees, 22.5 degrees, 22.9 degrees, 23.9 degrees, 24.4 degrees, 25.5 degrees, 26.2 degrees, 28.1 degrees, 29.3 degrees, 29.5 degrees, 30.6 degrees, 31.0 degrees and 31.5 degrees, which are consistent with the pattern 1. A DSC spectrum has a characteristic endothermic peak at 155.57 ℃, which is consistent with figure 2, TGA thermogravimetric analysis is carried out on the product, a Switzerland Torland TG A/DSC 1 type thermogravimetric analyzer is adopted, the atmosphere is nitrogen, the heating rate is 10 ℃/min, the TGA spectrum has no weight loss before the melting temperature, which is consistent with figure 3, and the obtained product is confirmed to be the dimethylamine michelia lactone fumarate C crystal form product. The product was in the form of a stick having a bulk density of 0.479g/ml, a purity of 99.07% and a yield of 92% similar to that of FIG. 4.
Example 2
Putting 3g of raw material of michelia lactone dimethylamine fumarate into a 150mL crystallizer, adding 100g of acetonitrile solvent to dissolve the raw material and keep the raw material in a supersaturated state, stirring the mixture at 50 ℃, carrying out solvent mediated crystal transformation, filtering the suspension after 48 hours to obtain a white solid, and drying the white solid at 40 ℃ under normal pressure for 10 hours to obtain the michelia lactone dimethylamine fumarate crystals. The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.6 degrees, 7.6 degrees, 11.8 degrees, 12.3 degrees, 13.3 degrees, 14.7 degrees, 15.3 degrees, 15.6 degrees, 16.0 degrees, 18.5 degrees, 18.8 degrees, 19.5 degrees, 20.7 degrees, 22.2 degrees, 27.1 degrees and 27.6 degrees, wherein 6.6 degrees is an initial peak, the relative intensity of the characteristic peaks at 7.6 degrees is 100 percent, and in addition, the X-ray powder diffraction pattern of the product also has characteristic peaks at 20.0 degrees, 22.7 degrees, 23.1 degrees, 24.1 degrees, 24.6 degrees, 25.7 degrees, 26.4 degrees, 28.3 degrees, 29.5 degrees, 30.7 degrees, 31.2 degrees and 31.7 degrees which are expressed by 2 theta angles and are consistent with the X-ray powder diffraction pattern 1. A DSC spectrum has a characteristic endothermic peak at 155.50 ℃, which is consistent with figure 2, TGA thermogravimetric analysis is carried out on the product, a Switzerland Torland TG A/DSC 1 type thermogravimetric analyzer is adopted, the atmosphere is nitrogen, the heating rate is 10 ℃/min, the TGA spectrum has no weight loss before the melting temperature, which is consistent with figure 3, and the obtained product is confirmed to be the dimethylamine michelia lactone fumarate C crystal form product. The product was in the form of a rod having a bulk density of 0.482g/ml, a purity of 99.15% and a yield of 93%, similar to that of FIG. 4.
Example 3
Putting 0.2g of raw material of the dimethylamine michelia lactone fumarate into a 20mL sample bottle, adding 10g of tetrahydrofuran solvent to dissolve the tetrahydrofuran solvent and enable the tetrahydrofuran solvent to be in a supersaturated state, stirring at 45 ℃, carrying out solvent-mediated crystal transformation, filtering the suspension after 30h to obtain a white solid, and drying at 35 ℃ under normal pressure for 8h to obtain the dimethylamine michelia lactone fumarate crystal. The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.3 degrees, 7.3 degrees, 11.4 degrees, 12.0 degrees, 13.0 degrees, 14.4 degrees, 15.0 degrees, 15.4 degrees, 15.8 degrees, 18.1 degrees, 18.5 degrees, 19.2 degrees, 20.4 degrees, 21.9 degrees, 26.9 degrees and 27.3 degrees, wherein 6.3 degrees is an initial peak, the relative intensity of the characteristic peaks at 7.3 degrees is 100 percent, and in addition, the diffraction angles of the X-ray powder diffraction pattern of the product expressed by 2 theta angles also have characteristic peaks at 19.8 degrees, 22.5 degrees, 22.8 degrees, 23.8 degrees, 24.4 degrees, 25.5 degrees, 26.2 degrees, 28.0 degrees, 29.2 degrees, 29.5 degrees, 30.6 degrees, 31.0 degrees and 31.5 degrees, which are consistent with the pattern 1. A DSC pattern has a characteristic endothermic peak at 153.10 ℃, which is consistent with figure 2, TGA thermogravimetric analysis is carried out on the product, a Switzerlington poly TG A/DSC 1 thermogravimetric analyzer is adopted, the atmosphere is nitrogen, the temperature rise rate is 10 ℃/min, the TGA pattern has no weight loss before the melting temperature, which is consistent with figure 2, and the obtained product is confirmed to be the dimethylamine smilactone fumarate C crystal form product. The product was in the form of a stick having a bulk density of 0.484g/ml, a purity of 99.28% and a yield of 90%, similar to that of FIG. 4.
Example 4
Putting 0.02g of raw material of the michelia lactone dimethylamine fumarate into a 4mL sample bottle, adding 2g of methyl isobutyl ketone solvent to dissolve the raw material and enable the raw material to be in a supersaturated state, stirring the mixture at 35 ℃, carrying out solvent mediated crystal transformation, filtering the suspension after 24h to obtain a white solid, and drying the white solid at 40 ℃ under normal pressure for 6h to obtain the michelia lactone dimethylamine fumarate crystals. The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.4 degrees, 7.4 degrees, 11.6 degrees, 12.1 degrees, 13.1 degrees, 14.5 degrees, 15.1 degrees, 15.5 degrees, 15.9 degrees, 18.3 degrees, 18.6 degrees, 19.3 degrees, 20.5 degrees, 22.0 degrees, 26.9 degrees and 27.4 degrees, wherein 6.4 degrees is an initial peak, the relative intensity of the characteristic peaks at 7.4 degrees is 100 percent, and in addition, the diffraction angles of the X-ray powder diffraction pattern of the product expressed by 2 theta angles also have characteristic peaks at 19.8 degrees, 22.5 degrees, 22.9 degrees, 23.9 degrees, 24.4 degrees, 25.5 degrees, 26.2 degrees, 28.1 degrees, 29.3 degrees, 29.5 degrees, 30.6 degrees, 31.0 degrees and 31.5 degrees, which are consistent with the pattern 1. A DSC pattern has a characteristic endothermic peak at 155.5 ℃, which is consistent with a figure 2, TGA thermogravimetric analysis is carried out on the product, a Switzerland toledo TG A/DSC 1 type thermogravimetric analyzer is adopted, the atmosphere is nitrogen, the temperature rise rate is 10 ℃/min, the TGA pattern has no weight loss before the melting temperature, which is consistent with a figure 3, and the obtained product is the product of the dimethylamine smilactone fumarate C crystal form. The product was a rod, similar to FIG. 4, with a bulk density of 0.479g/ml, a purity of 99.17% and a yield of 91.2%.
Example 5
Placing 0.4g of raw material of dimethylamine smilacin fumarate into a 20mL sample bottle, adding 10g of 1, 4-dioxane solvent to dissolve the dimethylamine smilacin fumarate into a supersaturated state, stirring at 35 ℃, carrying out solvent-mediated crystal transformation, filtering the suspension after 24h to obtain a white solid, and drying at 35 ℃ under normal pressure for 8h to obtain crystals of dimethylamine smilacin fumarate. The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.3 degrees, 7.3 degrees, 11.4 degrees, 12.0 degrees, 13.0 degrees, 14.4 degrees, 15.0 degrees, 15.4 degrees, 15.8 degrees, 18.1 degrees, 18.5 degrees, 19.2 degrees, 20.4 degrees, 21.9 degrees, 26.9 degrees and 27.3 degrees, wherein 6.3 degrees is an initial peak, the relative intensity of the characteristic peaks at 7.3 degrees is 100 percent, and in addition, the diffraction angles of the X-ray powder diffraction pattern of the product expressed by 2 theta angles also have characteristic peaks at 19.8 degrees, 22.5 degrees, 22.8 degrees, 23.8 degrees, 24.4 degrees, 25.5 degrees, 26.2 degrees, 28.0 degrees, 29.2 degrees, 29.5 degrees, 30.6 degrees, 31.0 degrees and 31.5 degrees, which are consistent with the pattern 1. And a DSC spectrum has a characteristic endothermic peak at 153 ℃, which is consistent with the figure 2, the TGA thermogravimetric analysis is carried out on the product, a Switzerland Mullerelopo TG A/DSC 1 type thermogravimetric analyzer is adopted, the atmosphere is nitrogen, the heating rate is 10 ℃/min, the TGA spectrum has no weight loss before the melting temperature, which is consistent with the figure 2, and the obtained product is the product of the C crystal form of the michelia lactone fumarate of dimethylamine. The product was a rod-like product having a bulk density of 0.484g/ml, a purity of 99.25% and a yield of 91%, similar to that of FIG. 4.
Example 6
Putting 9g of raw material of michelia lactone dimethylamine fumarate into a 200mL crystallizer, adding 150g of tetrahydrofuran solvent to dissolve the raw material and keep the raw material in a supersaturated state, stirring the mixture at 50 ℃, carrying out solvent mediated crystal transformation, filtering the suspension after 48 hours to obtain a white solid, and drying the white solid at 40 ℃ under normal pressure for 10 hours to obtain the michelia lactone dimethylamine fumarate crystal. The X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 6.6 degrees, 7.6 degrees, 11.8 degrees, 12.3 degrees, 13.3 degrees, 14.7 degrees, 15.3 degrees, 15.6 degrees, 16.0 degrees, 18.5 degrees, 18.8 degrees, 19.5 degrees, 20.7 degrees, 22.2 degrees, 27.1 degrees and 27.6 degrees, wherein 6.6 degrees is an initial peak, the relative intensity of the characteristic peaks at 7.6 degrees is 100 percent, and in addition, the X-ray powder diffraction pattern of the product also has characteristic peaks at 20.0 degrees, 22.7 degrees, 23.1 degrees, 24.1 degrees, 24.6 degrees, 25.7 degrees, 26.4 degrees, 28.3 degrees, 29.5 degrees, 30.7 degrees, 31.2 degrees and 31.7 degrees which are expressed by 2 theta angles and are consistent with the X-ray powder diffraction pattern 1. A DSC spectrum has a characteristic endothermic peak at 155.50 ℃, which is consistent with figure 2, TGA thermogravimetric analysis is carried out on the product, a Switzerland Torland TG A/DSC 1 type thermogravimetric analyzer is adopted, the atmosphere is nitrogen, the heating rate is 10 ℃/min, the TGA spectrum has no weight loss before the melting temperature, which is consistent with figure 3, and the obtained product is confirmed to be the dimethylamine michelia lactone fumarate C crystal form product. The product was in the form of a rod having a bulk density of 0.482g/ml, a purity of 99.2% and a yield of 94%, similar to that of FIG. 4.
Claims (5)
1. A crystal form C of michelia lactone fumarate of dimethylamine is characterized in that the diffraction angle of an X-ray powder diffraction pattern obtained by using Cu-K alpha ray measurement and expressed by a 2 theta angle has the initial peak values of +/-0.2 degrees, 7.4 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.1 +/-0.2 degrees, 13.1 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 18.3 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.5 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.5 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.9 +/-0.2 degrees, 24.4 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.2 degrees, 26.9 +/-0.2 degrees, 27.2 degrees, 22.9 +/-0.2 degrees, 22.2 degrees, 22.9 +/-0.2 degrees, 3.2 degrees, 3 +/-0.2 degrees, 31.6 +/-0.2 degrees, and 31.0 +/-0.0 degrees, wherein the relative peak values are 100 +/-0 degrees, +/-0 +/-0.2 degrees, +/-0 degree, +/-0.2 degrees, 0 degree and +/-0.3, 0.2 degrees, and +/-0.3.
2. The crystalline form C of michelia lactone fumarate of dimethylamine of claim 1, wherein the crystalline form is monoclinic, space group is P2(1), and unit cell parameters are a =13.136(3) a; b =6.2278(12) a; c =14.503(3) a; α is 90 °, β is 114.15(3) °, γ is 90 °, and the unit cell volume is 1082.6(4) a 3 。
3. The crystalline form C of michelia lactone fumarate of dimethylamine of claim 1, wherein said crystalline form C has a characteristic endothermic peak at 155 ± 2 ℃ as the melting peak of crystalline form C, has no weight loss before the melting temperature, and is a solvent-free compound.
4. The method of preparing crystalline form C of michelia lactone fumarate of dimethylamine of any of claims 1-3, wherein the crystalline form of michelia lactone fumarate is prepared by isothermal solvent-mediated transcrystallization: adding a solid raw material of the michelia lactone fumarate dimethylamine into a solvent with a constant temperature of 35-50 ℃ under the stirring action, wherein the mass ratio of the solid raw material of the michelia lactone fumarate dimethylamine to the solvent is 0.01-0.06:1, stirring for 24-48h, filtering, and drying to obtain a michelia lactone fumarate dimethylamine crystal form C crystal, wherein the crystal is a rod-shaped crystal habit;
the solvent is any one of acetone, acetonitrile, tetrahydrofuran, 1, 4-dioxane and methyl isobutyl ketone.
5. The method according to claim 4, wherein the drying is carried out at 30 to 40 ℃ under normal pressure for 6 to 10 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811515329.6A CN111303097B (en) | 2018-12-12 | 2018-12-12 | Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811515329.6A CN111303097B (en) | 2018-12-12 | 2018-12-12 | Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111303097A CN111303097A (en) | 2020-06-19 |
| CN111303097B true CN111303097B (en) | 2022-09-30 |
Family
ID=71152526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811515329.6A Active CN111303097B (en) | 2018-12-12 | 2018-12-12 | Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111303097B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220130212A (en) * | 2020-03-26 | 2022-09-26 | 아센다테크 | Hydrate of dimethylaminomicheliolide fumarate, preparation method and use thereof |
| CN113149946B (en) * | 2021-04-16 | 2022-11-29 | 天津大学 | Dimethylamine michelia lactone-m-hydroxybenzoate, and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127069A (en) * | 2010-01-20 | 2011-07-20 | 鲁南制药集团股份有限公司 | Tiotropium bromide crystal |
| CN103724307A (en) * | 2012-10-12 | 2014-04-16 | 天津尚德药缘科技有限公司 | Sphaelactone dimethylamine fumarate crystal form and preparation method thereof |
| CN104876899A (en) * | 2014-02-28 | 2015-09-02 | 天津尚德药缘科技股份有限公司 | Dimethylamino sphaelactone fumarate and use thereof |
| CN108727347A (en) * | 2017-04-14 | 2018-11-02 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of Opioid Receptors (MOR) agonist |
-
2018
- 2018-12-12 CN CN201811515329.6A patent/CN111303097B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127069A (en) * | 2010-01-20 | 2011-07-20 | 鲁南制药集团股份有限公司 | Tiotropium bromide crystal |
| CN103724307A (en) * | 2012-10-12 | 2014-04-16 | 天津尚德药缘科技有限公司 | Sphaelactone dimethylamine fumarate crystal form and preparation method thereof |
| CN104876899A (en) * | 2014-02-28 | 2015-09-02 | 天津尚德药缘科技股份有限公司 | Dimethylamino sphaelactone fumarate and use thereof |
| CN108727347A (en) * | 2017-04-14 | 2018-11-02 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of Opioid Receptors (MOR) agonist |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111303097A (en) | 2020-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6457658B2 (en) | Stable, solvate-free apremilast crystal form II and process for its production | |
| CN106008515A (en) | New crystal form of ibrutinib and preparation method of new crystal form | |
| CN111303097B (en) | Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof | |
| KR20150036336A (en) | Crystalline form i of tyrosine kinase inhibitor dimaleate and preparation methods thereof | |
| KR102522895B1 (en) | Crystal Form of JAK Kinase inhibitor Bisulfate and a preparation method therefor | |
| CN111303098B (en) | Sphaelactone dimethylamine fumarate crystal form E and preparation method thereof | |
| CN111303099B (en) | Sphaelactone dimethylamine fumarate crystal form F and preparation method thereof | |
| EP3366676B1 (en) | Crystalline forms of bedaquiline fumarate and preparation methods therefor | |
| WO2017161985A1 (en) | Crystal form of rebaudioside b and preparation process therefor and use thereof | |
| CN113166169A (en) | Novel crystalline forms of an MCL-1 inhibitor, process for their preparation and pharmaceutical compositions containing them | |
| WO2016101412A1 (en) | Crystallization water-free calcium dibutyryladenosine cyclophosphate crystal form, and preparation method and use thereof | |
| JP6761564B2 (en) | L-proline compound of sodium-glucose cotransporter 2 inhibitor, and monohydrate and crystal of L-proline compound | |
| CN106065016B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor | |
| CN114630668B (en) | Aprocitentan crystal form and preparation method and application thereof | |
| CN106336363B (en) | A kind of safinamide Mesylate Form C and preparation method thereof | |
| CN107311993A (en) | A kind of crystal formation II of canagliflozin and preparation method thereof | |
| EP3121188A1 (en) | Crystalline 3',5'-cyclic diguanylic acid | |
| CN108659037B (en) | Polymorphic substance of valproic acid phospholipid derivative and preparation method thereof | |
| CN106046084B (en) | Tylonolide acetone solvent compound and preparation method | |
| CN105085593A (en) | Regadenoson crystal form and preparation method thereof | |
| CN108570045A (en) | The crystal form of Anisodamine, preparation method, pharmaceutical composition | |
| CN103896833B (en) | Sorafenib p-methyl benzenesulfonic acid salt/solvate polymorph and preparation method thereof and purposes | |
| JPWO2017047791A1 (en) | New crystals of piperazine compounds | |
| CN109796400B (en) | Sorafenib tosylate crystal form and preparation method thereof | |
| EP3816176A1 (en) | Hydrate crystal of 3',3'-cgamp |
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 |