CN111675711A - Single crystal of Btk inhibitor compound and method for producing the same - Google Patents

Single crystal of Btk inhibitor compound and method for producing the same Download PDF

Info

Publication number
CN111675711A
CN111675711A CN201910182329.7A CN201910182329A CN111675711A CN 111675711 A CN111675711 A CN 111675711A CN 201910182329 A CN201910182329 A CN 201910182329A CN 111675711 A CN111675711 A CN 111675711A
Authority
CN
China
Prior art keywords
mtbe
solvent
single crystal
phenoxyphenyl
carboxamide
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
Application number
CN201910182329.7A
Other languages
Chinese (zh)
Inventor
刘军涛
杜争鸣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Baiji Shenzhou Suzhou Biotechnology Co ltd
Original Assignee
Baiji Shenzhou Suzhou Biotechnology Co ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Baiji Shenzhou Suzhou Biotechnology Co ltd filed Critical Baiji Shenzhou Suzhou Biotechnology Co ltd
Priority to CN201910182329.7A priority Critical patent/CN111675711A/en
Publication of CN111675711A publication Critical patent/CN111675711A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
    • C30B29/54—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
    • 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 present invention relates to a single crystal of (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide (compound 1) and a method for producing the same.

Description

Single crystal of Btk inhibitor compound and method for producing the same
Technical Field
The present invention relates to a single crystal of (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide and a method for preparing the same.
Background
International application WO2014173289 discloses a series of fused heterocyclic compounds as Btk inhibitors. Specifically, WO2014173289 discloses (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide (hereinafter referred to as compound 1),
Figure RE-GDA0002200472960000011
compound 1 is a potent, specific and irreversible BTK kinase inhibitor. Data generated using biochemical studies, cell-based studies, and animal studies in preclinical studies suggest that compound 1 may provide significant benefit in inhibiting tumor growth in B-cell malignancies. Since compound 1 showed greater selectivity than ibrutinib (ibrutinib) for inhibiting BTK against EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK and TEC, it is expected to produce fewer side effects than ibrutinib clinically. Preclinical safety evaluations demonstrated that compound 1 was safer than ibrutinib in overall tolerability and severe toxicity in single and repeated dose toxicity studies in both rats and dogs for up to 28 days. Furthermore, compound 1 has better bioavailability without accumulation problems than observed with ibrutinib. These unique properties warrant further evaluation of compound 1 in clinical studies.
Compound 1 has 1 chiral center. International application WO2018033853 discloses a polymorphic form of compound 1, and confirms that the absolute configuration of compound 1 is the S-configuration through its intermediates. In the above international application, a large number of solvent systems are used to screen compound 1 for its polymorphic form, and the results of the study show that the preparation of compound 1 in the crystalline state is very difficult and that compound 1 is not easily crystallized. This presents a significant challenge to growing single crystals of compound 1 to accurately characterize their crystal structure and determine their absolute configuration. Therefore, the acquisition and structure confirmation of the single crystal of compound 1 are of great significance to accurately characterize the crystalline state and absolute configuration of compound 1.
Summary of The Invention
The inventors of the present invention have unexpectedly obtained a single crystal of compound 1.
In a first aspect, the present application discloses a single crystal of compound 1 (also referred to as single crystal a) which is monoclinic, having space group P1.
Figure RE-GDA0002200472960000021
The unit cell parameters are as follows:
Figure RE-GDA0002200472960000022
α＝77.756(4)°，β＝82.545(4)°，γ＝68.655(3)°；Z＝2,
Figure RE-GDA0002200472960000023
Dc＝1.338g/cm3，F(000)＝
500.0, absorption coefficient mu 0.722mm-1The residual factor R value of the observable point [ I ≧ 2 σ ()I)]R1＝0.0288,wR20.0786; residual factor R value R of all diffraction points1＝0.0293,wR2＝0.0789。
In a second aspect, the present application discloses a method for preparing a single crystal of compound 1.
In a third aspect, the present application discloses that the single crystals disclosed herein can be used for characterization of the crystalline state of compound 1 and confirmation of its absolute configuration.
Brief Description of Drawings
Fig. 1 shows a schematic diagram of an asymmetric structural unit of the single crystal structure of compound 1.
FIG. 2 shows a diagram of atomic thermal vibration ellipsoids of molecules in the single crystal structure of Compound 1.
FIG. 3 shows a schematic diagram of a unit cell structure illustrating the single crystal structure of Compound 1.
Detailed Description
The inventors of the present invention carried out the cultivation of a single crystal of compound 1 using 23 solvent systems, and unexpectedly obtained a single crystal of compound 1. And it was found that not all solvent systems are capable of obtaining single crystals of compound 1 and are suitable for characterizing the absolute configuration of compound 1.
In some embodiments, the crystallization data and the crystallographic inclusion parameters of a single crystal of compound 1 of the present invention are set forth in table 1.
TABLE 1 crystallization data and Crystal pack parameters for single crystals of Compound 1
Figure RE-GDA0002200472960000031
The application also provides a preparation method of the single crystal. Single crystals disclosed herein can be prepared by crystallizing a compound disclosed herein from a suitable solvent system comprising at least one solvent, which can be achieved by spontaneous precipitation (evaporation), cooling, and/or addition of an anti-solvent, wherein the compound disclosed herein has a relatively low solubility, to achieve supersaturation in the solvent system. The single crystal may also be achieved with or without the use of seeds suitable for crystallizing the single crystals disclosed herein.
In some embodiments, the method for producing a single crystal of the present invention can be achieved by dissolving solid compound 1 or a crude crystal thereof in a solvent and volatilizing the solvent. Wherein the solvent includes, but is not limited to, IPAc, toluene, MeOH/MTBE (1:10), MeOH/H2O(1:1)、EtOH/H2O(1:2)、IPA/H2O (2:5), EtOAc/MTBE (1:1), EtOAc/n-heptane (2:1), IPAc/n-heptane (8:1) or ACN/H2O (1:2), and the dosage ratio of the solvent is volume ratio. Still further, the solvents include, but are not limited to, IPAc, toluene, MeOH/MTBE (1:10), EtOH/H2O (1:2), EtOAc/MTBE (1:1), EtOAc/n-heptane (2:1) or IPAc/n-heptane (8:1), the solvent being used in a volume ratio. Still further, the solvent is EtOH/H2O (1:2), and the using ratio of the solvent is volume ratio.
In some embodiments, the method of preparing a single crystal of the present invention is achieved by adding an anti-solvent to a solution of solid compound 1 or its crude crystalline form in a solvent for dissolving the solid. Wherein the anti-solvent includes, but is not limited to, methyl tert-butyl ether (MTBE) and the solvent used to dissolve the solid includes, but is not limited to, IPAc, MIBK, toluene, MeOH/MTBE (1:9), IPA/MTBE (2:5), EtOAc/MTBE (1:1), ACN/MTBE (1:5), CHCl3Any one of/MTBE (1:3) or acetone/MTBE (1:2), and the solvent is used in a volume ratio. Still further, the solvents include, but are not limited to, IPAc, MIBK, EtOAc/MTBE (1:1), ACN/MTBE (1:5), CHCl3Any one of/MTBE (1:3) and acetone/MTBE (1: 2).
In some embodiments, the method of preparing a single crystal of the present invention is accomplished by placing a solution of compound 1 or its crude crystalline form in a solvent, including but not limited to IPAc, MIBK, toluene, MeOH/MTBE (1:9), IPA/MTBE (2:5), EtOAc/MTBE (1:1), ACN/MTBE (1:5), CHCl, in an anti-solvent system and allowing sufficient time for the organics to evaporate to interact with the solution in the sealed reactor3Any one of/MTBE (1:3) or acetone/MTBE (1:2), the solvent is used in a volume ratio, and the anti-solvent includes but is not limited to methylTert-butyl ether (MTBE). Still further, the solvents include, but are not limited to, IPAc, MIBK, EtOAc/MTBE (1:1), ACN/MTBE (1:5), CHCl3Any one of/MTBE (1:3) and acetone/MTBE (1: 2).
In some embodiments, the method of preparing the single crystal is performed at room temperature. Wherein the room temperature is 18-25 ℃.
Definition of
Unless specifically defined otherwise in this document, all other 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.
Throughout the following description and claims, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The term "comprising" may be substituted with the term "comprising" as used herein, or sometimes with the term "having" as used herein.
Abbreviations
ACN Acetonitrile
CHCl3 Chloroform
EA Ethyl acetate, EtOAc
EtOH Ethanol
IPA Isopropanol (I-propanol)
IPAc Acetic acid isopropyl ester
MeOH Methanol
MIBK Methyl isobutyl ketone
MTBE Methyl tert-butyl ether
Examples
The invention is further illustrated by, but not limited to, the following examples which illustrate the invention.
The seed crystals of compound 1 described in the present invention can be prepared by the method described in international application WO 2018033853A.
Example 1
After 5.0mg of compound 1 was dissolved in the solvent described in table 2, followed by vortexing and sonication to accelerate dissolution, the suspension was filtered. Transferring the obtained filtrate to a clean single crystal bottle, adding a small amount of compound 1 as seed crystal, sealing with a PE-Plug single crystal bottle cap, pricking a small hole, standing, and slowly volatilizing at room temperature. The crystallization is shown in Table 2.
TABLE 2
Figure RE-GDA0002200472960000051
Figure RE-GDA0002200472960000061
Example 2
Compound 1 (about 5.0mg) was dissolved in the solvent described in Table 3, followed by vortexing and sonication to accelerate dissolution, and the suspension was filtered. The filtrate was transferred to a clean single crystal bottle, a small amount of compound 1 was added as a seed crystal, and then sealed with a PE-Plug single crystal cap and a small hole was punched, and placed in a 20mL glass bottle containing 3mL of methyl tert-butyl ether (MTBE) as an anti-solvent, and naturally volatilized and diffused at room temperature. The crystallization is shown in Table 3.
TABLE 3
Serial number Solvent (v/v) Anti-solvent Temperature (. degree.C.)) Crystallization behavior
1 IPAc MTBE RT Bulk crystal (Small particle)
2 MIBK MTBE RT Bulk crystal (Small particle)
3 Toluene MTBE RT Irregular crystal (Small particle)
4 MeOH/MTBE(1:9) MTBE RT Solid body
5 IPA/MTBE(2:5) MTBE RT Irregular crystal (Small particle)
6 EtOAc/MTBE(1:1) MTBE RT Bulk crystal (Small particle)
7 ACN/MTBE(1:5) MTBE RT Bulk crystal
8 CHCl3/MTBE(1:3) MTBE RT Irregular solid
9 acetone/MTBE (1:2) MTBE RT Bulk crystal (Small particle)
10 anisole/MTBE (1:2) MTBE RT Clarifying solvent
EXAMPLE 3 Single Crystal X-ray diffraction (SCXRD) experiment of Compound 1 Single Crystal
From the crystals prepared in examples 1 and 2, crystals suitable for single crystal X-ray diffraction test were selected and further analyzed and examined.
When the crystal particles are small, a more suitable single crystal can be formed by extending the solvent volatilization time. For example, in example 1, EtOH/H was used2And (3) culturing the single crystal by using an O (1:2) system, slowly volatilizing for 6 days to obtain oil drops and colloidal substances (wherein the colloidal substances wrap a plurality of small crystals), and slowly volatilizing for 14 days to obtain a blocky single crystal sample.
Instruments and their parameters:
agilent SuperNova diffractometer (SperNova (Cu) X-ray source,
Figure RE-GDA0002200472960000075
an EosCCD detector).
Figure RE-GDA0002200472960000071
The single crystal is a triclinic system, space group P1, and the unit cell parameters are as follows:
Figure RE-GDA0002200472960000072
Figure RE-GDA0002200472960000073
α＝77.756(4)°,β＝82.545(4)°,γ＝68.655(3)°,
Figure RE-GDA0002200472960000074
the molecular weight is 471.55 g-mol-1, Z is 2, and the density calculation value Dc is 1.338 g-cm-3. The detailed crystallization data and parameters are shown in table 1.
The asymmetric unit of the single crystal structure consists of two compound 1 molecules independent of the crystal, as shown in fig. 1, indicating that the crystal is an anhydrous compound of compound 1. The atomic thermal vibration ellipsoid diagrams of two compound 1 molecules in an asymmetric unit are shown in FIG. 2. The absolute configuration assignment (R/S) of the chiral atom in the compound 1 is { C1(S) }. The single cell structure of the single crystal structure is shown in FIG. 3.

Claims (10)

  1. (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-A ]]A single crystal of pyrimidine-3-carboxamide, characterized in that it belongs to the triclinic system, the space group being P1, and the unit cell parameters being:
    Figure FDA0001991404530000011
    Figure FDA0001991404530000012
    α＝77.756(4)°，β＝82.545(4)°，γ＝68.655(3)°；Z＝2，
    Figure FDA0001991404530000013
    Dc＝1.338g/cm3。
  2. 2. the single crystal of claim 1, wherein said single crystal has an F (000) ═ 500.0, and an absorption coefficient μ ═ 0.722mm-1Residual factor R value of observable point [ I ≧ 2 sigma (I)]R1＝0.0288，wR20.0786; residual factor R value R of all diffraction points1＝0.0293，wR2＝0.0789。
  3. 3. A method of preparing the single crystal of any one of claims 1-2, comprising the steps of: mixing (S) -7- (1-acryloyl piperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydro pyrazolo [1, 5-A)]Dissolving pyrimidine-3-carboxamide in a solvent, standing the solution, and crystallizing to obtain crystals, wherein the solvent is optionally selected from IPAc, toluene, MeOH/MTBE (1:10), MeOH/H2O(1∶1)、EtOH/H2O(1∶2)、IPA/H2O(2∶5)、EtOAc/MTBE (1:1), EtOAc/n-heptane (2:1), IPAc/n-heptane (8:1) or ACN/H2O (1:2), and the dosage ratio of the solvent is volume ratio.
  4. 4. A method of preparing the single crystal of any one of claims 1-2, comprising the steps of: mixing (S) -7- (1-acryloyl piperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydro pyrazolo [1, 5-A)]Dissolving pyrimidine-3-carboxamide in a solvent, standing the resulting solution, and crystallizing to obtain crystals, wherein the solvent is optionally selected from IPAc, toluene, MeOH/MTBE (1:10), EtOH/H2O (1:2), EtOAc/MTBE (1:1), EtOAc/n-heptane (2:1) or IPAc/n-heptane (8:1), the solvents being used in a volume ratio.
  5. 5. A method of preparing the single crystal of any one of claims 1-2, comprising the steps of: mixing (S) -7- (1-acryloyl piperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydro pyrazolo [1, 5-A)]Dissolving pyrimidine-3-formamide in a solvent, standing the obtained solution, and crystallizing to obtain crystals, wherein the solvent is EtOH/H2O (1:2), and the dosage ratio of the solvent is volume ratio.
  6. 6. A method of preparing the single crystal of any one of claims 1-2, comprising the steps of: mixing (S) -7- (1-acryloyl piperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydro pyrazolo [1, 5-A)]Dissolving pyrimidine-3-carboxamide in a solvent, placing the resulting solution in a system of anti-solvent methyl tert-butyl ether (MTBE), standing, and crystallizing to obtain crystals, wherein the solvent is optionally selected from IPAc, MIBK, toluene, MeOH/MTBE (1:9), IPA/MTBE (2:5), EtOAc/MTBE (1:1), ACN/MTBE (1:5), CHCl3Any one of/MTBE (1:3) or acetone/MTBE (1:2), and the solvent is used in a volume ratio.
  7. 7. A method of preparing the single crystal of any one of claims 1-2, comprising the steps of: mixing (S) -7- (1-acryloyl piperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyridineAzolo [1,5-A]Dissolving pyrimidine-3-carboxamide in a solvent, placing the resulting solution in a system of anti-solvent methyl tert-butyl ether (MTBE), standing, and crystallizing to obtain crystals, wherein the solvent is optionally selected from IPAc, MIBK, EtOAc/MTBE (1:1), ACN/MTBE (1:5), CHCl3Any one of/MTBE (1:3) or acetone/MTBE (1:2), and the solvent is used in a volume ratio.
  8. 8. The production process according to any one of claims 3 to 7, characterized in that (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-A ] pyrimidine-3-carboxamide is dissolved in a solvent, and the resulting solution is further seeded.
  9. 9. The process according to any one of claims 3 to 8, wherein (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-A ] pyrimidine-3-carboxamide may be in the form of crude crystals.
  10. 10. The production process according to any one of claims 3 to 9, wherein the temperature condition for the standing is room temperature.
CN201910182329.7A 2019-03-11 2019-03-11 Single crystal of Btk inhibitor compound and method for producing the same Pending CN111675711A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910182329.7A CN111675711A (en) 2019-03-11 2019-03-11 Single crystal of Btk inhibitor compound and method for producing the same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910182329.7A CN111675711A (en) 2019-03-11 2019-03-11 Single crystal of Btk inhibitor compound and method for producing the same

Publications (1)

Publication Number Publication Date
CN111675711A true CN111675711A (en) 2020-09-18

Family

ID=72451224

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910182329.7A Pending CN111675711A (en) 2019-03-11 2019-03-11 Single crystal of Btk inhibitor compound and method for producing the same

Country Status (1)

Country Link
CN (1) CN111675711A (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018033853A2 (en) * 2016-08-16 2018-02-22 Beigene, Ltd. Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018033853A2 (en) * 2016-08-16 2018-02-22 Beigene, Ltd. Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
陈润锋等: "《有机化学与光电材料实验教程》", vol. 1, 东南大学出版社, pages: 288 - 289 *

Similar Documents

Publication Publication Date Title
HRP20120217A2 (en) Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof
CN108864077A (en) The solid form and preparation method thereof of jamaicin acylate
KR100399765B1 (en) Crystalline Macrolides and Process for Their Preparation
CN112390812A (en) Crystalline and amorphous solids of Ruogeli compounds and methods of making the same
EP2342195B1 (en) Crystalline forms of a 3-pyrrole substituted 2-indolinone malate salt
CN113149992B (en) Preparation method and application of midazolam hydrochloride F crystal form
CN111675711A (en) Single crystal of Btk inhibitor compound and method for producing the same
CN103059013B (en) Crystal formation of Dasatinib monohydrate and preparation method thereof
CN109956896B (en) Spiro [ cyclopropane-1, 3-indoline ] framework, crystal thereof, preparation method and application thereof
CN111406046B (en) Polymorphic form of tebuconazole and preparation method thereof
KR102617156B1 (en) New polymorphic form of minocycline base and method for preparing the same
WO2016067054A1 (en) Processs for the formation of hydrocodone bitatrate
CN110804080A (en) Acetaminoavermectin crystal form A, crystal form B, amorphous and preparation method thereof
CN107868117B (en) Stenazole saccharinate and preparation method and application thereof
CN110964017A (en) Polymorph of Ribociclib monosuccinate and preparation method and application thereof
TWI768595B (en) An efficient crystallization process for preparing ultrapure treprostinil and crystal prepared therefrom
CN109734726B (en) Refining method of cefixime trihydrate crystals
CN117430655A (en) Novel propionyl brassinolide crystal form, and preparation method and application thereof
CN107043405B (en) Crystal form of polycyclic heterocyclic compound, preparation method, application and composition thereof
CN116444385A (en) Crystal of meta-hydroxylamine bitartrate, preparation method and application
CN117263938A (en) Novel crystal form of avibactam monosodium salt
KR20180050451A (en) Preparation Method for Crystalline L-α-Glyceryl Phosphoryl Choline
CN117700354A (en) Crystal form of raffinancin and preparation method thereof
CN117003689A (en) Crystal form of iodophosphate and preparation method thereof
CN115611921A (en) Oxacillin acid amine salt and related crystal form

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