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 PDFInfo
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- 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
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 title description 5
- 229940124291 BTK inhibitor Drugs 0.000 title description 3
- RNOAOAWBMHREKO-QFIPXVFZSA-N (7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)[C@@H]1CCNC=2N1N=C(C=2C(=O)N)C1=CC=C(C=C1)OC1=CC=CC=C1 RNOAOAWBMHREKO-QFIPXVFZSA-N 0.000 claims abstract description 5
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- 238000000034 method Methods 0.000 claims description 12
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- 238000010521 absorption reaction Methods 0.000 claims description 2
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- 229940125904 compound 1 Drugs 0.000 abstract description 34
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 9
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- 238000010586 diagram Methods 0.000 description 4
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- 230000001788 irregular Effects 0.000 description 3
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
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- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000892986 Homo sapiens Tyrosine-protein kinase FRK Proteins 0.000 description 1
- 101000912503 Homo sapiens Tyrosine-protein kinase Fgr Proteins 0.000 description 1
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- 101000889732 Homo sapiens Tyrosine-protein kinase Tec Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
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- 238000009825 accumulation Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- ARQRPTNYUOLOGH-UHFFFAOYSA-N chcl3 chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)Cl ARQRPTNYUOLOGH-UHFFFAOYSA-N 0.000 description 1
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- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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
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),
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.
The unit cell parameters are as follows:
α＝77.756(4)°，β＝82.545(4)°，γ＝68.655(3)°；Z＝2,
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
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
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,
an EosCCD detector).
The single crystal is a triclinic system, space group P1, and the unit cell parameters are as follows:
α＝77.756(4)°,β＝82.545(4)°,γ＝68.655(3)°,
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)
- (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:α＝77.756(4)°，β＝82.545(4)°，γ＝68.655(3)°；Z＝2，Dc＝1.338g/cm3。
- 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. 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. 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. 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. 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. 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. 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. 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. The production process according to any one of claims 3 to 9, wherein the temperature condition for the standing is room temperature.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| 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)
| 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 * |
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