CN109963855B - Crystal form of BTK kinase inhibitor and preparation method thereof - Google Patents
Crystal form of BTK kinase inhibitor and preparation method thereof Download PDFInfo
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The invention relates to a crystal form of a BTK kinase inhibitor and a preparation method thereof. Utensil for cleaning buttockIn particular, the present invention relates to (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d]A II-type crystal of pyridazine-7-ketone (compound shown in a formula (I)) and a preparation method thereof. The II-type crystal of the compound of the formula (I) obtained by the invention has good chemical stability and crystal form stability, and the used crystallization solvent has low toxicity and low residue, and can be better used for clinical treatment.
Description
Technical Field
The invention relates to a crystal form and a preparation method of a BTK kinase inhibitor, in particular to a type II crystal of (R) -1- (1-acryloyl piperidine-3-yl) -4-amino-3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazine-7-ketone and a preparation method thereof. The compounds of formula (I) prepared according to the process of the invention are useful in the treatment of B-cell malignancies and autoimmune diseases.
Background
Bruton's tyrosine protein kinase (BTK) is a non-receptor cytoplasmic tyrosine kinase belonging to Tec family of kinases, where Tec family kinase members also include Tec, Itk, Txk and Bmx, most of which are predominantly expressed in hematopoietic cells. BTK is crucial for B cell development, differentiation, maturation and signaling. Loss-of-function mutations in BTK cause X-linked agammaglobulinemia (XLA) in humans and X-associated immunodeficiency in mice. XLA patients have a normal pre-B cell population in their bone marrow, but these cells fail to mature and enter the circulation. Thus, these patients also had essentially no circulating B cells and were unable to produce antibodies. BTK plays a critical role in B cell proliferation and activation mediated by the B Cell Receptor (BCR). For BCR activation, BTK translocates to the plasma membrane, which is phosphorylated, followed by initiation of signaling events including activation of phospholipase C γ 2(PLC γ 2), ultimately leading to calcium mobilization and transcriptional regulation involving nuclear factor κ B. Because of the indispensable role in the BCR signaling pathway, the kinase activity of BTK is critical for the development and repair of various B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL) and some subtypes of non-hodgkin's lymphoma (critical non-hodgkin's lymphoma), Mantle Cell Lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). In addition, the role of B cells in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and other immune diseases has been clinically demonstrated. Thus, targeting the small molecule inhibitor BTK is beneficial in the treatment of B cell malignancies and autoimmune diseases.
WO2016/007185 relates to a compound of formula (I), namely (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one, which is a novel BTK kinase inhibitor, with improvements in kinase selectivity, clinical efficacy or indications and safety. However, no study was made on the crystalline form of the compound in this patent.
CN106939002A discloses an amorphous form and a crystal form I of the compound of formula (I), but both of the amorphous form and the crystal form I have the problem of poor stability, so it is necessary to improve various properties of the product, and a better crystal form needs to be found.
Disclosure of Invention
The invention provides a II-type crystal of (R) -1- (1-acryloyl piperidine-3-yl) -4-amino-3- (4- (2, 6-difluoro phenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazine-7-ketone (shown in a formula (I)) and a preparation method thereof,
a series of crystal products are obtained by the compound shown in the formula (I) under different crystallization conditions, and X-diffraction and DSC detection are carried out on the obtained crystal products, so that the compound shown in the formula (I) can obtain a crystal form with good stability under the conventional crystallization conditions, and the crystal form is called as type II crystal. The DSC pattern of the type II crystal in the present application shows a melting endothermic peak at around 165 ℃ and, using Cu-Ka radiation, an X-ray powder diffraction pattern is obtained which is expressed by 2 theta angles and interplanar spacings (d values) and which has characteristic peaks at diffraction angles 2 theta angles of 4.64, 5.18, 5.62, 11.43, 12.21 and 20.47, wherein the error range of 2 theta angles of each characteristic peak is. + -. 0.2.
Further, the crystal was irradiated with Cu-Ka to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta angles having characteristic peaks at 4.64, 5.18, 5.62, 11.13, 11.43, 12.21, 12.87, 14.03, 19.60, 20.47 and 24.16 in terms of diffraction angle 2 theta angles, wherein the error range of 2 theta angles of each characteristic peak was. + -. 0.2.
Further, the crystal has an X-ray powder diffraction pattern as shown in fig. 3, and has diffraction angle 2 θ angles in the range of 4.64(19.04), 5.18(17.05), 5.62(15.71), 8.11(10.89), 8.99(9.83), 10.34(8.55), 11.13(7.94), 11.43(7.74), 12.21(7.24), 12.87(6.87), 14.03(6.31), 14.47(6.12), 14.86(5.96), 15.63(5.66), 16.07(5.51), 16.49(5.37), 17.78(4.98), 18.40(4.82), 19.60(4.53), 20.47(4.34), 21.31(4.17), 24.16(3.68), 25.13(3.54), 26.87(3.32) and 28.50 (3.50), wherein each of the diffraction angle 2 θ angles is characterized by a peak error of ± 0 θ characteristic range.
The present invention also provides a method for preparing form II crystals of (R) -1- (1-acryloylpiperidin-3-yl) -4-amino-3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one. The method comprises the following steps:
(1) dissolving a compound shown in the formula (I) with any crystal form or amorphous form in a proper amount of organic solvent, or carrying out crystal transformation, cooling and crystallization on the compound shown in the formula (I) with any crystal form or amorphous form in the organic solvent, wherein the organic solvent is acetonitrile.
(2) The crystals were filtered, washed and dried.
The method of recrystallization is not particularly limited, and the recrystallization can be carried out by a usual recrystallization operation method. For example, the compound represented by the formula (I) as a raw material is dissolved in an organic solvent under heating, then gradually cooled to crystallize, and after completion of crystallization, the desired crystal can be obtained by filtration and drying. In particular, the filtered crystals are usually dried under reduced pressure under vacuum at about 30 to 100 ℃ and preferably at 40 to 60 ℃ to remove the recrystallization solvent.
The crystal form of the obtained compound crystal shown as the formula (I) is researched by differential scanning thermal analysis (DSC) and X-diffraction pattern measurement, and the solvent residue of the obtained crystal is detected.
The compound II crystal prepared by the method of the invention does not contain or only contains a lower content of residual solvent, meets the limit requirement of the residual solvent of related medical products specified by the national pharmacopoeia, and therefore, the crystal of the invention can be better used as a medical active ingredient.
Research shows that the II-type crystal of the compound shown in the formula (I) prepared by the invention has good stability under the conditions of illumination, high temperature and high humidity, and has good crystal form stability under the conditions of grinding, pressure, heating and the like, so that the medicinal requirements of production, transportation and storage can be met, the production process is stable, repeatable and controllable, and the preparation method can be suitable for industrial production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of an amorphous sample of a compound of formula (I).
FIG. 2 is a DSC chart of an amorphous sample of the compound of formula (I).
FIG. 3 is an X-ray powder diffraction pattern of a form II crystal of the compound represented by the formula (I).
FIG. 4 is a DSC chart of form II crystals of the compound represented by the formula (I).
FIG. 5 is an X-ray powder diffraction pattern of Compound I form crystal represented by formula (I).
FIG. 6 is a DSC chart of form I crystals of the compound represented by the formula (I).
FIG. 7 is a DVS diagram of a form I crystal of a compound represented by the formula (I).
FIG. 8 is a DVS diagram of a form II crystal of a compound represented by the formula (I).
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test instrument for experiments
1. DSC spectrum
The instrument model is as follows: mettler Toledo DSC 1 STARe System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 40-250 deg.C
2. X-ray diffraction spectrum
The instrument model is as follows: bruker D8 Focus X-ray powder diffractometer
Ray: monochromatic Cu-ka radiation (λ ═ 1.5406)
The scanning mode is as follows: θ/2 θ, scan range: 2-40 °
Voltage: 40kV, current: 40mA
Example 1
5g of the compound of formula (I) (prepared as disclosed in WO 2016/007185) was placed in a 100ml single-neck flask, 50ml of acetonitrile was added, the mixture was heated until the solid was completely dissolved, cooled and crystallized, and stirred overnight. The next day, filtration and drying were carried out to obtain 4.03g of solid with a yield of 80.6%. The crystalline sample was characterized by X-ray diffraction as shown in fig. 3, wherein peaks were characterized at about 4.64(19.04), 5.18(17.05), 5.62(15.71), 8.11(10.89), 8.99(9.83), 10.34(8.55), 11.13(7.94), 11.43(7.74), 12.21(7.24), 12.87(6.87), 14.03(6.31), 14.47(6.12), 14.86(5.96), 15.63(5.66), 16.07(5.51), 16.49(5.37), 17.78(4.98), 18.40(4.82), 19.60(4.53), 20.47(4.34), 21.31(4.17), 24.16(3.68), 25.13(3.54), 26.87(3.32) and 28.50 (3.13). The DSC spectrum is shown in figure 4, and a melting endothermic peak is formed around 165 ℃, and the crystal form is defined as the II crystal form.
Example 2
300mg of the compound represented by the formula (I) (prepared by the method disclosed in WO 2016/007185) was put into a 25ml single-neck flask, 2ml of ethanol was added, the mixture was dissolved by heating, crystallized by cooling, and stirred overnight. The next day, filtration and drying were carried out to obtain 241mg of solid with a yield of 80.3%. The crystalline sample was X-ray diffracted as shown in fig. 5, wherein characteristic peaks were found at about 4.29(20.56), 6.58(13.42), 7.58(11.66), 10.07(8.78), 10.72(8.24), 11.68(7.57), 12.49(7.08), 13.74(6.44), 14.12(6.26), 15.86(5.58) and 19.98 (4.44). The DSC spectrum is shown in figure 6, and a melting endothermic peak is formed at the temperature of about 141 ℃, and the crystal form is defined as I crystal form.
Example 3
200mg of the compound of the formula (I) (prepared as in example 2) was taken, 2ml of acetonitrile was added, and the mixture was stirred overnight. The next day, filtration and drying were carried out to obtain 172mg of a solid with a yield of 86.0%. The X-ray diffraction and DSC pattern of the crystallization sample are compared by research to determine that the product is II crystal form.
Example 4
Samples of the crystalline product form II obtained in example 1 and the crystalline product form I obtained in example 2 were placed open and left to stand, and the stability of the samples was examined under conditions of light (4500Lux), heat (40 ℃, 60 ℃), high humidity (RH 75%, RH 90%). The sampling times were considered to be 5 days and 10 days, and the purity by HPLC was found to be shown in Table 1.
Comparison of the stabilities of the samples of the form I and II of the Compound of formula (I) shown in Table 1
The stability examination result shows that the type I crystal and the type II crystal of the compound shown in the formula (I) are respectively placed under an open condition, the stability of the type II crystal is better than that of the type I crystal under the conditions of illumination and high temperature, and the type I crystal and the type II crystal are equivalent under the high-humidity condition.
Example 5
The compound II crystal of formula (I) prepared in example 1 was ground, heated and tabletted, and the results of the study showed that the crystal form was stable, and the detailed experimental data are shown in table 2 below.
Table 2, study on the specific stability of the crystal form II of the compound represented by the formula (I)
Example 6
DVS tests were conducted on the type II crystal product samples obtained in example 1 and the type I crystal product samples obtained in example 2 at 25 ℃ and different humidity, and the research results show that the crystal form I has larger hygroscopicity, the RH increases by 4.18% when the RH is 0-80%, the water absorption is about 3.26% under the normal storage condition (namely 25 ℃, RH 60%), the crystal form II has hygroscopicity, the weight increases by 1.18% when the RH is 0-80%, the water absorption is about 0.93% under the normal storage condition (namely 25 ℃, RH 60%), and detailed experimental data are shown in FIGS. 7 and 8.
Claims (7)
1. Form II crystals of a compound of formula (I) characterized by: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta angles, wherein the diffraction angle 2 theta angles of the X-ray powder diffraction pattern have characteristic peaks at 4.64, 5.18, 5.62, 11.43, 12.21 and 20.47, the error range of each characteristic peak 2 theta angle is +/-0.2,
2. the form II crystal of the compound of formula (I) according to claim 1, characterized in that: using Cu-Ka radiation, obtaining an X-ray powder diffraction pattern expressed by diffraction angle 2 theta angles, wherein the diffraction angle 2 theta angles of the X-ray powder diffraction pattern have characteristic peaks at 4.64, 5.18, 5.62, 11.13, 11.43, 12.21, 12.87, 14.03, 19.60, 20.47 and 24.16, and the error range of the 2 theta angle of each characteristic peak is +/-0.2.
3. The form II crystal of the compound represented by the formula (I) according to claim 1, characterized by having characteristic peaks at diffraction angles 2 θ of 4.64, 5.18, 5.62, 8.11, 8.99, 10.34, 11.13, 11.43, 12.21, 12.87, 14.03, 14.47, 14.86, 15.63, 16.07, 16.49, 17.78, 18.40, 19.60, 20.47, 21.31, 24.16, 25.13, 26.87 and 28.50, wherein the error range of 2 θ angle of each characteristic peak is. + -. 0.2.
4. The form II crystal of the compound of formula (I) according to claim 3, characterized by having an X-ray powder diffraction pattern as shown in figure 3.
5. A process for preparing form II crystals of a compound of formula (I) as defined in any one of claims 1 to 4, comprising the steps of:
1) dissolving a compound shown as a formula (I) in any crystal form or amorphous form in a proper amount of organic solvent, cooling and crystallizing, or carrying out crystal transformation on the compound shown as the formula (I) in any crystal form or amorphous form in the organic solvent, wherein the organic solvent is acetonitrile;
2) the crystals were filtered, washed and dried.
6. A pharmaceutical composition comprising the form II crystal of the compound represented by the formula (I) as claimed in any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
7. Use of the form II crystal of any one of claims 1 to 4 or the pharmaceutical composition of claim 6 for the preparation of a medicament for the treatment of B-cell malignancies and autoimmune diseases.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710573824 | 2017-07-14 | ||
| CN2017105738241 | 2017-07-14 | ||
| PCT/CN2018/095573 WO2019011316A1 (en) | 2017-07-14 | 2018-07-13 | Crystalline form of btk kinase inhibitor and preparation method therefor |
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| CN109963855A CN109963855A (en) | 2019-07-02 |
| CN109963855B true CN109963855B (en) | 2021-09-03 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106573001A (en) * | 2014-07-07 | 2017-04-19 | 永恒生物科技公司 | Aminopyridazinone compounds as protein kinase inhibitors |
| CN106939002A (en) * | 2016-01-05 | 2017-07-11 | 江苏恒瑞医药股份有限公司 | A kind of crystal form of BTK kinase inhibitors and preparation method thereof |
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- 2018-07-13 CN CN201880004377.0A patent/CN109963855B/en active Active
- 2018-07-13 WO PCT/CN2018/095573 patent/WO2019011316A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106573001A (en) * | 2014-07-07 | 2017-04-19 | 永恒生物科技公司 | Aminopyridazinone compounds as protein kinase inhibitors |
| CN106939002A (en) * | 2016-01-05 | 2017-07-11 | 江苏恒瑞医药股份有限公司 | A kind of crystal form of BTK kinase inhibitors and preparation method thereof |
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| CN109963855A (en) | 2019-07-02 |
| TW201908320A (en) | 2019-03-01 |
| WO2019011316A1 (en) | 2019-01-17 |
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