CN112876530A - Crystal form of dydrogesterone intermediate and preparation method thereof - Google Patents
Crystal form of dydrogesterone intermediate and preparation method thereof Download PDFInfo
- Publication number
- CN112876530A CN112876530A CN201911200510.2A CN201911200510A CN112876530A CN 112876530 A CN112876530 A CN 112876530A CN 201911200510 A CN201911200510 A CN 201911200510A CN 112876530 A CN112876530 A CN 112876530A
- Authority
- CN
- China
- Prior art keywords
- degrees
- dydrogesterone
- crystal form
- preparation
- crystalline 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.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- 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
Abstract
The invention provides a pregna-5, 7-diene-3, 20-diethylene glycol ketal crystal form and a preparation method thereof. The crystal form provided by the invention is relatively stable under high temperature, high humidity and illumination, and can well avoid crystal transformation and product degradation in the processes of intermediate storage and subsequent use. The invention also provides a preparation method of the crystal form, which is simple, convenient, good in reproducibility and suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a crystal form of a dydrogesterone intermediate and a preparation method thereof.
Background
Dydrogesterone is 6-dehydro-progesterone, an oral progestational hormone, and can make endometrium enter into complete secretion phase, thereby preventing endometrium hyperplasia and canceration risk caused by estrogen. The chemical structure of the progesterone is closest to that of natural progesterone, but the in vivo biological activity of the progesterone is higher than that of the natural progesterone; the oral administration of the composition is effective at low dose, and has no effects of estrogen, androgen and adrenocorticoid; does not generate heat, has no influence on lipid metabolism, and has better safety and tolerance.
Pregna-5, 7-diene-3, 20-diethylene glycol ketal is a key intermediate for preparing dydrogesterone, and the structural formula of the pregna-5, 7-diene-3, 20-diethylene glycol ketal is shown as the formula (I):
the compound of formula I can be prepared by protecting progesterone with ethylene glycol, brominating, and debrominating. It is well known in the art that crystalline materials are generally more stable than their amorphous state. Therefore, the present inventors hope to find suitable crystals at the intermediate stage of dydrogesterone to make the compound of formula I more stable during storage.
There is no report on the crystal form of the compound of formula I, and it is desired to obtain crystals with good stability and high purity for the final use of the compound as a therapeutic or as an intermediate of dydrogesterone, and therefore, it is necessary to perform a comprehensive and systematic polymorphic screening to select a crystal form suitable for development.
Disclosure of Invention
The invention aims to provide a crystal form A of a dydrogesterone intermediate with a structure shown in a formula I. Specifically, the invention provides a crystal form A of a dydrogesterone intermediate with a structure shown in a formula I, wherein an X-ray powder diffraction pattern of the crystal form A at least comprises two characteristic peaks at the following 2 theta angles: 12.06 +/-0.2 degrees, 14.44 +/-0.2 degrees, 15.56 +/-0.2 degrees, 16.62 +/-0.2 degrees, 18.70 +/-0.2 degrees, 20.68 +/-0.2 degrees, 23.52 +/-0.2 degrees, 26.78 +/-0.2 degrees and 29.76 +/-0.2 degrees;
further, the crystal form A of the dydrogesterone intermediate has peaks at the following 2 theta angles on an X-ray powder diffraction pattern detected by Cu-Kalpha radiation: 12.04 +/-0.2 degrees, 14.44 +/-0.2 degrees, 15.56 +/-0.2 degrees, 16.62 +/-0.2 degrees, 18.70 +/-0.2 degrees, 20.68 +/-0.2 degrees, 23.52 +/-0.2 degrees, 26.78 +/-0.2 degrees and 29.76 +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern of the crystal form A provided by the invention is shown in figure 1.
Preferably, the differential scanning calorimetry analysis chart of the crystal form A provided by the invention shows that the endothermic peak begins to appear when the crystal form A is reheated to be about 202 ℃.
Further preferably, the crystalline form a provided by the present invention, when heated to around 230 ℃, has no weight loss, and its thermogravimetric analysis (TGA) is shown in figure 3;
further, the present invention provides crystalline form a as an anhydrate which is a nonsolvent.
The invention also provides a preparation method of the crystal form A of the dydrogesterone intermediate with the structure shown in the formula I, which comprises the following steps: heating and dissolving a dydrogesterone intermediate in a solvent;
(b) cooling to-20-30 ℃, separating out solids, filtering and drying to obtain a crystal form A of the dydrogesterone intermediate;
in the above method, the solvent in step (a) is selected from one or more of methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, dichloromethane and chloroform; preferably, the solvent is a mixed solution of acetone and one or more selected from methanol, ethanol, ethyl acetate, tetrahydrofuran, dichloromethane and chloroform, and more preferably, the solvent is a mixed solvent of dichloromethane and acetone;
the heating temperature is 35-100 ℃, preferably 40-80 ℃, and more preferably 50-60 ℃;
preferably, in the step (b), the temperature is reduced to-10-20 ℃, and more preferably, the temperature is reduced to 0-10 ℃.
Further, in order to provide the yield, after the solid is preferably precipitated, heat-preservation crystallization is continued for a period of time, preferably, heat-preservation crystallization is carried out for 5-20 hours, further preferably, 6-8 hours, and the drying time in the step (b) is 1-20 hours, preferably, 4-6 hours; researches find that the cooling speed has no influence on the purity and the crystal form basically.
Further, in the above method, the amount of acetone used in step (a) is 85% to 98% of the total volume of the solvent, preferably 90% to 95% of the total volume of the solvent.
Preferably, the solvent used in step (a) is a mixed solution of dichloromethane and acetone; wherein the volume ratio of the dichloromethane to the acetone is 1: 5-1: 50, preferably, the volume ratio of the dichloromethane to the acetone is 1: 10-1: 15; further preferably, the dosage ratio of the dydrogesterone intermediate in the step (a) to the solvent is 1: 1.5-3 (g/ml), preferably 1: 8-2 (g/ml).
Further, cooling to 0-10 ℃ in the step (b), separating out solids, and continuously crystallizing for 5-20 hours at the temperature of 0-10 ℃; the drying time is 1-20 hours; more preferably, the temperature in the step (b) is controlled to be 0-10 ℃ and crystallization is continued for 6-8 hours; the drying time is 4-6 hours.
The 'dydrogesterone intermediate', 'compound of formula I' and 'dydrogesterone intermediate with the structure shown in formula I' all refer to compounds with the structure shown in formula I:
the dydrogesterone is only produced by the original research at present, and due to the limitation of the process difficulty, the dydrogesterone is not successfully imitated at home and abroad, so that the report is relatively few.
The compound of the formula I is amorphous and has poor stability under acid and alkali, oxidation reduction, high temperature and high humidity and illumination, the crystal form A provided by the invention is relatively stable under high temperature and high humidity and illumination, and crystal transformation and product degradation can be well avoided in the storage and subsequent use processes of the intermediate. The crystal form A of the compound of the formula I provided by the invention has low hygroscopicity, is not easily influenced by humidity, has no strict requirement on storage conditions, is convenient for long-term storage, greatly reduces the cost in the aspects of material storage and quality control, and has very high economic value.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of a crystal form A of a dydrogesterone intermediate obtained in example 1;
FIG. 2 is a DSC spectrum of the crystal form A of the dydrogesterone intermediate obtained in example 1;
FIG. 3 is a TGA spectrum of crystalline form A of the dydrogesterone intermediate obtained in example 1;
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The technical solutions of the present invention are further described below with specific examples, but the scope of the present invention is not limited thereto. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
The analysis and detection conditions of the invention are as follows:
the X-ray powder diffraction pattern of the invention is collected on a D8ADVANCE X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:
x-ray reflectance parameters: cu, K-alpha radiation;
Kα1：1.5406；Kα2：1.54443；
the K alpha 2/K alpha 1 intensity ratio: 0.50;
voltage: 36 kilovolts (kV);
current: 20 milliamperes (mA);
scanning range: from 5.0 to 60.0 degrees;
step length: 0.02 degree.
The Differential Scanning Calorimetry (DSC) chart of the invention is collected on a NETZSCH 204. The parameters of the Differential Scanning Calorimetry (DSC) method are as follows:
the heating rate is as follows: 1 ℃/min;
scanning range: 1.0-900.0 ℃;
protective gas: nitrogen gas.
Thermogravimetric analysis (TGA) profiles described herein were collected on NETZSCH TG 209. The process parameters for thermogravimetric analysis (TGA) described in the present invention are as follows:
the heating rate is as follows: 1 ℃/min;
scanning range: 1.0-900.0 ℃;
protective gas: nitrogen gas.
Example 1 preparation of crystalline form a of a chrysophasterone intermediate
Sequentially adding 20g of dydrogesterone intermediate, 5ml of dichloromethane and 50ml of acetone into a reaction bottle, heating to 50-60 ℃, carrying out heat preservation and reflux reaction for 1h, and slowly cooling to 0-10 ℃ for crystallization for 6-8 h. And (3) carrying out suction filtration, washing a filter cake by using 10ml of cooled acetone, and carrying out forced air drying on the filter cake at 50-60 ℃ to constant weight to obtain 18g of white-like crystals, wherein the HPLC purity is 99.80%, and the yield is 90%.
The obtained crystal was subjected to X-ray powder diffraction (XRPD) analysis (see FIG. 1), DSC analysis (see FIG. 2) and TGA analysis (see FIG. 3) and was crystalline form A.
Example 2 preparation of crystalline form a of a chrysophasterone intermediate
Sequentially adding 30g of dydrogesterone intermediate, 5ml of trichloromethane and 50ml of acetone into a reaction bottle, heating to 60-70 ℃, carrying out heat preservation reflux reaction for 1h, and slowly cooling to 0-10 ℃ for crystallization for 6-8 h. And (3) carrying out suction filtration, washing a filter cake by using 10ml of cooled acetone, and carrying out forced air drying on the filter cake at 50-60 ℃ to constant weight to obtain 17.2g of white-like crystals, wherein the HPLC purity is 99.85%, and the yield is 86%. Detected as crystal form A.
Example 3 preparation of crystalline form a of a chrysophasterone intermediate
And sequentially adding 30g of dydrogesterone intermediate, 5ml of tetrahydrofuran and 70ml of acetone into a reaction bottle, heating to 60-70 ℃, carrying out heat preservation reflux reaction for 1h, and slowly cooling to 0-10 ℃ for crystallization for 6-8 h. And (3) carrying out suction filtration, washing a filter cake by using 10ml of cooled acetone, and carrying out forced air drying on the filter cake at 50-60 ℃ to constant weight to obtain 18.2g of white-like crystals, wherein the HPLC purity is 99.91% and the yield is 91%. Detected as crystal form A.
Example 4 preparation of crystalline form a of a chrysophasterone intermediate
And sequentially adding 30g of dydrogesterone intermediate, 5ml of ethyl acetate and 70ml of acetone into a reaction bottle, heating to 60-70 ℃, carrying out heat preservation reflux reaction for 1h, and slowly cooling to 0-10 ℃ for crystallization for 6-8 h. And (3) carrying out suction filtration, washing a filter cake by using 10ml of cooled acetone, and carrying out forced air drying on the filter cake at 50-60 ℃ to constant weight to obtain 17.6g of white-like crystals, wherein the HPLC purity is 99.82%, and the yield is 88%. Detected as crystal form A.
Example 5 hygroscopicity assay of the dydrogesterone intermediate form a:
a dry glass tare bottle (50 mm external diameter, high 15mm) was weighed out precisely (19.0034g) one day before the test in a climatic chamber (set temperature 25 ℃ C. + -1 ℃ C., relative humidity 80% Shi 2%). An appropriate amount of the crystal form A prepared in example 1 was taken as a test sample, and the test sample was spread in the above weighing bottle, and the thickness of the test sample was about 1mm, and the weight was precisely weighed (20.0020 g). The weighing bottle is opened and is placed under the constant temperature and humidity condition for 24 hours together with the bottle cap. The bottle cap was weighed and the weight was precisely weighed (20.0102 g).
Percent weight gain (20.0102g-20.0020g)/(20.0020g-19.0034 g). times.100% -0.82%
Definition of hygroscopicity increase (Chinese pharmacopoeia 2015 year edition appendix 9103 medicine hygroscopicity test guiding principle, experimental conditions: 25 ℃ ± 1 ℃, 80% relative humidity):
deliquescence: sufficient water is absorbed to form a liquid.
Has the characteristics of moisture absorption: the moisture-drawing weight gain is not less than 15%.
Moisture absorption: the moisture-inducing weight gain is less than 15% but not less than 2%.
Slightly hygroscopic: the moisture-inducing weight gain is less than 2% but not less than 0.2%.
No or almost no hygroscopicity: the moisture-drawing weight gain is less than 0.2 percent.
The result shows that the weight of the crystal form A is increased by 0.82 percent after the crystal form A is balanced under the relative humidity of 80 percent, and the crystal form A is slightly hygroscopic.
The crystal form A prepared in the examples 2 to 5 is tested by the same method for hygroscopicity, and the weight gain percentage is between 0.80 and 0.85 percent, which is slightly hygroscopicity.
Example crystalline form a of the intermediate of hexadrogesterone was compared to amorphous powders in a high temperature, high humidity and high light test:
the detection method comprises the following steps:
the measuring column is a C18 column with the specification of 4.6mm multiplied by 250mm multiplied by 5um and the column temperature is 40 ℃; mobile phase a [ 0.02M ammonium dihydrogen phosphate solution (with 0.1% triethylamine, pH 7.0 adjusted with phosphoric acid) ]: acetonitrile 90: 10(V/V), 100% acetonitrile of a B phase, and adopting gradient elution, wherein the table of the gradient elution is shown in the following table, and the flow rate is 1.0 mL/min; the detector is VWD, and the detection wavelength is 280 nm; the sample was dissolved in tetrahydrofuran and made into a solution of about 500ug/mL in a 20uL volume.
Test protocol: the samples were placed at 40 ℃, 60 ℃ and humidity RH 72.0%, RH 92.0% and under high light conditions for 10 days, and were removed on days 5 and 10 for the measurement by the above-mentioned method, and compared with the untreated sample solution.
Content and purity data under high temperature and high humidity illumination conditions
The result shows that the crystal form A is more stable than amorphous form under high temperature, high humidity and strong light; form a and amorphous form are both unstable and degrade rapidly under strong acid and strong base redox conditions, so this data is not presented.
Claims (10)
1. The crystal form A of the dydrogesterone intermediate with the structure shown in the formula I is characterized in that an X-ray powder diffraction pattern of the crystal form A at least comprises two characteristic peaks at the following 2 theta angles: 12.06 +/-0.2 degrees, 14.44 +/-0.2 degrees, 15.56 +/-0.2 degrees, 16.62 +/-0.2 degrees, 18.70 +/-0.2 degrees, 20.68 +/-0.2 degrees, 23.52 +/-0.2 degrees, 26.78 +/-0.2 degrees and 29.76 +/-0.2 degrees;
2. crystalline form a of a dydrogesterone intermediate according to claim 1 having an X-ray powder diffraction pattern with peaks at the following 2 Θ angles: 12.04 +/-0.2 degrees, 14.44 +/-0.2 degrees, 15.56 +/-0.2 degrees, 16.62 +/-0.2 degrees, 18.70 +/-0.2 degrees, 20.68 +/-0.2 degrees, 23.52 +/-0.2 degrees, 26.78 +/-0.2 degrees and 29.76 +/-0.2 degrees.
3. Crystalline form a of the dydrogesterone intermediate according to claim 1, wherein the crystalline form a shows no weight loss by thermogravimetric analysis when heated to around 230 ℃; differential scanning calorimetry analysis showed that form a started to show an endothermic peak when reheated to around 202 ℃.
4. Crystalline form a of a dydrogesterone intermediate according to claim 1, characterized in that it is anhydrous and non-solvated.
5. Crystalline form a of a dydrogesterone intermediate according to claim 1, characterized in that the crystalline form a has an X-ray powder diffraction pattern as shown in figure 1.
6. A preparation method of a crystal form A of a dydrogesterone intermediate with a structure shown in a formula I comprises the following steps:
(a) heating and dissolving the dydrogesterone intermediate in a solvent; the solvent is a mixed solution of acetone and one or more selected from methanol, ethanol, ethyl acetate, tetrahydrofuran, dichloromethane and trichloromethane;
(b) and cooling to 0-10 ℃, separating out solids, filtering and drying to obtain the crystal form A of the dydrogesterone intermediate.
7. The method according to claim 6, wherein the solvent in the step (a) is selected from a mixed solution of dichloromethane and acetone.
8. The preparation method according to claim 6, wherein the temperature in the step (b) is reduced to 0-10 ℃, solids are separated out, and the temperature is controlled to be 0-10 ℃ to continue crystallization for 5-20 hours; the drying time is 1-20 hours.
9. The preparation method according to claim 8, wherein the temperature in the step (b) is controlled to be 0-10 ℃ and crystallization is continued for 6-8 hours; the drying time is 4-6 hours.
10. Use of the crystalline form A of the dydrogesterone intermediate of any one of claims 1 to 4 for the preparation of dydrogesterone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911200510.2A CN112876530A (en) | 2019-11-29 | 2019-11-29 | Crystal form of dydrogesterone intermediate and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911200510.2A CN112876530A (en) | 2019-11-29 | 2019-11-29 | Crystal form of dydrogesterone intermediate and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112876530A true CN112876530A (en) | 2021-06-01 |
Family
ID=76038537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911200510.2A Pending CN112876530A (en) | 2019-11-29 | 2019-11-29 | Crystal form of dydrogesterone intermediate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112876530A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114057820A (en) * | 2021-11-15 | 2022-02-18 | 湖南科瑞生物制药股份有限公司 | Refining method of dydrogesterone |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013078575A1 (en) * | 2011-12-02 | 2013-06-06 | 台州市海盛化工有限公司 | New preparation method of 5,7-pregnadiene-3,20-dione-diethyl ketal |
-
2019
- 2019-11-29 CN CN201911200510.2A patent/CN112876530A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013078575A1 (en) * | 2011-12-02 | 2013-06-06 | 台州市海盛化工有限公司 | New preparation method of 5,7-pregnadiene-3,20-dione-diethyl ketal |
Non-Patent Citations (1)
| Title |
|---|
| ROSE ANTONUCCI ET AL: ""Δ5, 7-STEROIDS. XIII. STEROIDAL CYCLIC KETALS. II1, 2 THEPREPARATION OF A417-PREGNADIENE-32, 0-DIONE AND Δ4, 7-PREGNADIEKE-21-OL2-03-DIONE-ACETATE"", 《THE JOURNAL OF ORGANIC CHEMISTRY》, pages 1369 - 1374 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114057820A (en) * | 2021-11-15 | 2022-02-18 | 湖南科瑞生物制药股份有限公司 | Refining method of dydrogesterone |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114174284A (en) | Crystalline salt forms of 6- (cyclopropanecarboxamido) -4- ((2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d 3) pyridazine-3-carboxamide | |
| CN112876530A (en) | Crystal form of dydrogesterone intermediate and preparation method thereof | |
| CN104829673B (en) | A kind of preparation method of rope fluorine cloth Wei crystal formation 6 | |
| CN109776417B (en) | Bulleyaconitine A G crystal form and preparation method and application thereof | |
| CN109734664B (en) | Bulleyaconitine A D crystal form and preparation method and application thereof | |
| CN109824595B (en) | Bulleyaconitine A E crystal form and preparation method and application thereof | |
| CN109776416B (en) | Bulleyaconitine A C crystal form and preparation method and application thereof | |
| KR102528854B1 (en) | Crystal form of mesaconine and its preparation method | |
| WO2016101412A1 (en) | Crystallization water-free calcium dibutyryladenosine cyclophosphate crystal form, and preparation method and use thereof | |
| CN108794383B (en) | Eutectic of nifedipine and isonicotinamide | |
| CN116621828A (en) | Crystal forms of oxazolidinone derivative, preparation method and application thereof | |
| CN108727417B (en) | Polycyclic compound sodium salt, and polycrystalline type, preparation method and application thereof | |
| CN112375093A (en) | Keliboro crystal form compound and preparation method thereof | |
| CN110291071B (en) | Crystal form of SB-939 salt, preparation method and application thereof | |
| CN115785048B (en) | GL-V9 crystal form and preparation method thereof | |
| CN111320601B (en) | Oroxylin crystal form and preparation method thereof | |
| CN114716433B (en) | Crystal form of demethylenetetrahydroberberine hydrochloride and preparation method thereof | |
| CN116514697A (en) | Piracetam polymorphic form and preparation method thereof | |
| CN114276358B (en) | Polymorphs of oxycodone hydrochloride, preparation method and application thereof | |
| KR20190071715A (en) | Aldosterone synthase inhibitor | |
| CN115947699B (en) | Epalrestat eutectic crystal taking nicotinamide as precursor and preparation method thereof | |
| CN107739358B (en) | Daidzein anhydrous crystal form II, preparation method and medical application thereof | |
| WO2023190663A1 (en) | High-purity compound production method and purification method | |
| CN117263849A (en) | Crystal form of raffinacine trihydrate and preparation method thereof | |
| CN116283919A (en) | Novel crystal form of Vimseltinib and preparation method thereof |
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 |