阅读说明：本技术 巴洛沙韦新晶型及其制备方法 (Barosavir new crystal form and preparation method thereof ) 是由 郑保富 李硕梁 金飞敏 刘钢 曹铭 陈玉凤 于 2020-06-15 设计创作，主要内容包括：本发明涉及多种巴洛沙韦(Baloxavir marboxil,式Ⅰ)的新晶型及其制备方法。与现有技术相比,本发明制备得到的新晶型具有溶解性好、引湿性小、工艺稳定、可操作性强、收率高、制备可重现性好,而且所得晶型稳定,适合医药开发等优点。<Image he="355" wi="350" file="DDA0002538944160000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a plurality of new crystal forms of Baloxavir (Baloxavir marboxil, a formula I) and a preparation method thereof. Compared with the prior art, the novel crystal form prepared by the invention has the advantages of good solubility, small hygroscopicity, stable process, strong operability, high yield, good reproducibility of preparation, stable crystal form, suitability for medicine development and the like.)

1. A crystal form VII of Barosavir is characterized in that an X-ray powder diffraction pattern of the crystal form VII has characteristic peaks at 2theta values of 4.22 +/-0.2 degrees, 8.34 +/-0.2 degrees, 20.66 +/-0.2 degrees, 22.92 +/-0.2 degrees, 24.84 +/-0.2 degrees and 33.32 +/-0.2 degrees.

2. The crystalline form VII of claim 1, characterized by an X-ray powder diffraction pattern substantially in accordance with fig. 3.

3. The preparation method of the crystal form VII according to claims 1 and 2, characterized by comprising the following steps:

(1) dissolving a solid of baroxavir in tetrahydrofuran;

(2) and cooling, separating out crystals, and filtering to obtain a solid, namely the crystal form VII.

4. A crystal form VIII of baroxavir is characterized in that an X-ray powder diffraction pattern of the crystal form VIII has characteristic peaks at 2theta values of 8.66 +/-0.2 degrees, 9.06 +/-0.2 degrees, 10.04 +/-0.2 degrees, 10.70 +/-0.2 degrees, 20.00 +/-0.2 degrees, 20.50 +/-0.2 degrees, 21.50 +/-0.2 degrees, 22.52 +/-0.2 degrees, 23.42 +/-0.2 degrees, 24.58 +/-0.2 degrees, 25.64 +/-0.2 degrees, 29.12 +/-0.2 degrees and 31.66 +/-0.2 degrees.

5. The crystalline form VIII of claim 4 having an X-ray powder diffraction pattern substantially in accordance with FIG. 5.

6. A method for preparing crystalline form VIII according to claims 4 and 5, characterized in that it comprises the following steps:

(1) adding the solid of the baroxavir into a mixed solvent of acetonitrile and water;

(2) heating to dissolve, and stirring;

(3) cooling to room temperature, and standing until crystals are separated out;

(4) filtering and drying to obtain solid crystal form VIII.

7. A crystal form IX of Barosavir is characterized in that an X-ray powder diffraction pattern of the crystal form IX has characteristic peaks at 2theta values of 9.10 +/-0.2 degrees, 18.04 +/-0.2 degrees, 22.54 +/-0.2 degrees, 24.56 +/-0.2 degrees and 31.70 +/-0.2 degrees.

8. A crystalline form IX according to claim 7, characterized in that its X-ray powder diffraction pattern substantially corresponds to that of figure 7.

9. A process for the preparation of crystalline form IX according to claims 7, 8, characterized in that it comprises the following steps:

(1) adding the solid of the baroxavir into a mixed solvent of acetonitrile and water;

(2) heating to dissolve, and stirring;

(3) dropwise adding water under stirring;

(4) cooling to room temperature, stirring, filtering, and drying the solid to obtain crystal form IX.

10. A1: 2 baroxavir azomethylpyrrolidone solvate XII is characterized in that an X-ray powder diffraction pattern thereof has characteristic peaks at 2theta values of 8.66 +/-0.2 degrees, 9.06 +/-0.2 degrees, 10.04 +/-0.2 degrees, 10.70 +/-0.2 degrees, 20.00 +/-0.2 degrees, 20.50 +/-0.2 degrees, 21.50 +/-0.2 degrees, 22.52 +/-0.2 degrees, 23.42 +/-0.2 degrees, 24.58 +/-0.2 degrees, 25.64 +/-0.2 degrees, 29.12 +/-0.2 degrees and 31.66 +/-0.2 degrees.

11. Solvate XII according to claim 10, characterised in that it has an X-ray powder diffraction pattern substantially in accordance with FIG. 13.

12. The process for the preparation of a solvate XII of 1:2 Barosavir azomethylpyrrolidone, according to claims 10 and 11, comprising the steps of:

(1) adding the baroxavir solid to the N-methylpyrrolidone;

(2) heating to dissolve and clear;

(3) and (4) performing rotary evaporation and drying to obtain a solid, namely a solvate XII.

Technical Field

The invention relates to the field of chemical medicine, in particular to a novel baroxavir crystal form for resisting influenza and a preparation method thereof.

Background

Barosavir (Baloxavir marboxil, shown in formula I) is discovered by Japanese salt-sense pharmacy (Shionogi Co), developed together with Roche (Roche), and is approved by the FDA for treating influenza A and B viruses in 2018, 10 and 24 days, and is the first anti-influenza drug approved by the FDA and using a new mechanism. The structure of the drug molecule is shown as follows:

so far, only the original patent WO2018030463A1 reports the crystal form I, the crystal form II and the crystal form III of the crystal form of the baroxavir.

The X-ray powder diffraction patterns of the crystal form I, the crystal form II and the crystal form III disclosed by the patent are as follows:

in addition, the patent discloses that the X-ray powder diffraction of the Barosavir crystal form I has characteristic peaks at 2theta values of 8.6 +/-0.2 degrees, 14.1 +/-0.2 degrees, 17.4 +/-0.2 degrees, 20.0 +/-0.2 degrees, 24.0 +/-0.2 degrees, 26.3 +/-0.2 degrees, 29.6 +/-0.2 degrees and 35.4 +/-0.2 degrees. However, the characteristic peaks of the disclosed form I are not completely consistent with the spectrum.

Through research, the new crystal forms of the baroxavir are obtained, namely the crystal forms V, VII, VIII, IX, X, XI and XII.

Disclosure of Invention

The invention aims to provide a plurality of new baroxavir crystal forms and a preparation method of each crystal form. These crystalline forms can be produced using the methods described herein and are substantially free of other crystalline forms. The term "substantially free" means that the content of the other form is 10% or less, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5% or less.

The crystal form can be analyzed by X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC) spectrum, thermogravimetric analysis (TGA) and nuclear magnetic resonance hydrogen spectrum (X-ray powder diffraction-induced diffraction (XRPD) (XRPD)), and the like¹H NMR) was performed.

It is an object of the present invention to provide crystalline form v of balosavir.

The crystal form V of the baroxavir provided by the invention is characterized in that characteristic peaks exist at 2theta values of 8.66 +/-0.2 degrees, 9.02 +/-0.2 degrees, 17.96 +/-0.2 degrees, 22.48 +/-0.2 degrees, 24.54 +/-0.2 degrees and 31.64 +/-0.2 degrees in an XRPD pattern.

Further, the crystal form v of baroxavir provided by the invention is characterized in that the XRPD pattern also has characteristic peaks at 2 θ values of 4.60 ± 0.2 °, 17.50 ± 0.2 °, 19.04 ± 0.2 °, 20.46 ± 0.2 °, 21.46 ± 0.2 °, 28.20 ± 0.2 ° and 30.26 ± 0.2 °.

Further, the present invention provides crystalline form v of baroxavir further characterized by an XRPD pattern substantially in accordance with figure 1.

Further, the present invention provides crystalline form v of baroxavir characterized by an endothermic peak at about 239.1 ℃ upon heating, which DSC profile substantially corresponds to figure 2.

It is another object of the present invention to provide a process for the preparation of crystalline form v of basosavir.

Furthermore, the preparation method of the crystal form V of the baroxavir is characterized by comprising the following steps:

(1) adding the solid of the baroxavir into a mixed solvent of acetonitrile and water;

(2) heating to dissolve, and stirring;

(3) cooling to room temperature, and standing;

(4) stirring at room temperature, filtering, and collecting the solid to obtain the crystal form V.

The mixed solvent of acetonitrile and water in the step (1) is characterized in that the ratio of acetonitrile to water is preferably (8-12): 1, more preferably 10: 1.

In the step (2), the dissolving temperature is preferably 55-65 ℃, and more preferably 60 ℃.

Another object of the present invention is to provide a crystalline form vii of baroxavir.

The crystal form VII of the baroxavir provided by the invention is characterized in that characteristic peaks are provided at 2theta values of 4.22 +/-0.2 degrees, 8.34 +/-0.2 degrees, 20.66 +/-0.2 degrees, 22.92 +/-0.2 degrees, 24.84 +/-0.2 degrees and 33.32 +/-0.2 degrees in an XRPD pattern.

Furthermore, the crystal form VII of the baroxavir provided by the invention is characterized in that the XRPD pattern also has characteristic peaks at 2theta values of 8.98 +/-0.2 degrees, 16.52 +/-0.2 degrees, 26.72 +/-0.2 degrees, 29.08 +/-0.2 degrees and 31.66 +/-0.2 degrees.

Further, the present invention provides crystalline form vii of baroxavir which is further characterized by an XRPD pattern substantially in accordance with fig. 3.

Further, the invention provides a crystalline form VII of Barosavir which is characterized by an endothermic peak at about 236.7 ℃ upon heating and which has a DSC/TGA profile substantially in accordance with FIG. 4.

Another object of the present invention is to provide a process for the preparation of crystalline balosavir form vii.

Furthermore, the preparation method of the crystal form VII of the baroxavir is characterized by comprising the following steps:

(1) dissolving a solid of baroxavir in tetrahydrofuran;

(2) and cooling, separating out crystals, and filtering to obtain a solid, namely the crystal form VII.

In the step (1), the dissolving temperature is preferably 45-55 ℃, and more preferably 50 ℃.

In the step (2), the crystallization temperature is preferably-15 to-25 ℃, and more preferably-20 ℃.

It is another object of the present invention to provide a crystalline form viii of balosavir.

The crystal form VIII of the baroxavir provided by the invention is characterized in that characteristic peaks are provided at 2theta values of 8.66 +/-0.2 degrees, 9.06 +/-0.2 degrees, 10.04 +/-0.2 degrees, 10.70 +/-0.2 degrees, 20.00 +/-0.2 degrees, 20.50 +/-0.2 degrees, 21.50 +/-0.2 degrees, 22.52 +/-0.2 degrees, 23.42 +/-0.2 degrees, 24.58 +/-0.2 degrees, 25.64 +/-0.2 degrees, 29.12 +/-0.2 degrees and 31.66 +/-0.2 degrees in an XRPD pattern.

Further, the crystalline form viii of baroxavir provided by the present invention is further characterized by having characteristic peaks at 2 θ values of 4.42 ± 0.2 °, 11.74 ± 0.2 °, 17.14 ± 0.2 °, 18.04 ± 0.2 °, 19.62 ± 0.2 °, 27.56 ± 0.2 °, and 34.54 ± 0.2 ° in the XRPD pattern.

Further, the present invention provides crystalline form viii of balosavir which is further characterized by an XRPD pattern substantially in accordance with fig. 5.

Further, the invention provides a crystalline form viii of balosavir characterized by a small endothermic peak at around 71.4 ℃ due to acetonitrile solvent residue, and an endothermic peak at around 238.4 ℃ upon heating, and having a DSC/TGA profile substantially in accordance with that of fig. 6.

It is another object of the present invention to provide a process for the preparation of crystalline form viii of baloxavir.

Furthermore, the preparation method of the Barosavir crystal form VIII is characterized by comprising the following steps of:

(1) adding the solid of the baroxavir into a mixed solvent of acetonitrile and water;

(2) heating to dissolve, and stirring;

(3) cooling to room temperature, and standing until crystals are separated out;

(4) filtering and drying to obtain solid crystal form VIII.

The mixed solvent of acetonitrile and water in the step (1) is characterized in that the ratio of acetonitrile to water is preferably (8-12): 1, more preferably 10: 1.

In the step (2), the dissolving temperature is preferably 55-65 ℃, and more preferably 60 ℃.

It is another object of the present invention to provide a crystalline form IX of baroxavir.

The crystal form IX of the baroxavir provided by the invention is characterized in that characteristic peaks are provided at 2theta values of 9.10 +/-0.2 degrees, 18.04 +/-0.2 degrees, 22.54 +/-0.2 degrees, 24.56 +/-0.2 degrees and 31.70 +/-0.2 degrees in an XRPD pattern.

Further, the invention provides a crystal form IX of baroxavir, which is characterized in that the XRPD pattern also has characteristic peaks at 2theta values of 4.64 +/-0.2 degrees, 20.52 +/-0.2 degrees, 26.26 +/-0.2 degrees, 26.66 +/-0.2 degrees, 28.22 +/-0.2 degrees and 30.32 +/-0.2 degrees.

Further, the present invention provides crystalline form ix of baroxavir further characterized in that the XRPD pattern thereof is substantially in accordance with fig. 7.

Further, the present invention provides a crystalline form ix of baroxavir characterized by the appearance of an endothermic peak near 237.9 ℃ upon heating, the DSC/TGA diagram substantially corresponding to figure 8.

Another object of the present invention is to provide a process for the preparation of crystalline form ix of baroxavir.

Furthermore, the invention provides a preparation method of the crystal form IX of the baroxavir, which is characterized by comprising the following steps:

(1) adding the solid of the baroxavir into a mixed solvent of acetonitrile and water;

(2) heating to dissolve, and stirring;

(3) dropwise adding water under stirring;

(4) cooling to room temperature, stirring, filtering, and drying the solid to obtain crystal form IX.

The mixed solvent of acetonitrile and water in the step (1) is characterized in that the ratio of acetonitrile to water is preferably (8-12): 1, more preferably 10: 1.

In the step (2), the dissolving temperature is preferably 65-75 ℃, and more preferably 70 ℃.

It is a further object of the present invention to provide a crystalline form x of baroxavir.

The crystal form X of the baroxavir provided by the invention is characterized in that characteristic peaks exist at 2theta values of 4.36 +/-0.2 degrees, 8.44 +/-0.2 degrees, 8.96 +/-0.2 degrees, 20.44 +/-0.2 degrees, 22.54 +/-0.2 degrees, 24.42 +/-0.2 degrees and 26.72 +/-0.2 degrees in an XRPD pattern.

Further, the invention provides a crystalline form x of baroxavir which is characterized by having characteristic peaks in the XRPD pattern at 2 θ values of 17.66 ± 0.2 °, 20.76 ± 0.2 °, 22.96 ± 0.2 °, 28.42 ± 0.2 °.

Further, the present invention provides crystalline form x of baroxavir further characterized by an XRPD pattern substantially in accordance with figure 9.

Further, the present invention provides crystalline form x of baroxavir characterized by an endothermic peak at about 223.5 ℃ upon heating, the DSC diagram of which is substantially in accordance with figure 10.

It is another object of the present invention to provide a process for the preparation of crystalline form x of baroxavir.

Furthermore, the preparation method of the crystal form X of the baroxavir is characterized by comprising the following steps:

(1) dissolving a solid of baroxavir in tetrahydrofuran;

(2) concentrating until solid is separated out;

(3) cooling, and dripping water;

(4) the solid obtained by filtering is the crystal form X.

In the step (2), the concentration temperature is preferably 40-45 ℃, and more preferably 40 ℃.

In the operation of the step (3), the dropping temperature is preferably 15-25 ℃, and more preferably 20 ℃.

It is another object of the invention to provide crystalline form xi of baloxavir.

The crystalline form XI of the baroxavir provided by the invention is characterized in that characteristic peaks are provided at 2theta values of 9.10 +/-0.2 degrees, 9.44 +/-0.2 degrees, 17.82 +/-0.2 degrees, 18.40 +/-0.2 degrees, 19.44 +/-0.2 degrees, 20.94 +/-0.2 degrees, 21.94 +/-0.2 degrees, 22.84 +/-0.2 degrees and 24.94 +/-0.2 degrees in an XRPD diagram.

Furthermore, the crystal form XI of the baroxavir provided by the invention is characterized in that the XRPD pattern also has characteristic peaks at 2theta values of 4.88 +/-0.2 degrees, 11.16 +/-0.2 degrees, 15.32 +/-0.2 degrees, 19.76 +/-0.2 degrees, 26.04 +/-0.2 degrees and 28.54 +/-0.2 degrees.

Further, the invention provides crystalline form xi of baroxavir which is characterized in that the XRPD pattern is substantially in accordance with fig. 11.

Furthermore, the crystal form XI of the baroxavir provided by the invention is characterized in that an endothermic peak appears when the crystal form XI is heated to 226.0 ℃, and a DSC chart of the crystal form XI is basically consistent with that of figure 12.

Another object of the invention is to provide a process for the preparation of baroxavir form xi.

Furthermore, the preparation method of the baroxavir crystal form XI provided by the invention is characterized by comprising the following steps:

(1) dissolving the crystalline form X solid of the baroxavir in a mixed solvent of acetonitrile and water;

(2) stirred and filtered to obtain solid form XI.

The mixed solvent of acetonitrile and water in the step (1) is characterized in that the ratio of acetonitrile to water is preferably (0.9-1.1): 1, more preferably 1: 1.

In the operation of the step (2), the stirring temperature is preferably 23-28 ℃, and more preferably 25 ℃.

It is another object of the invention to provide a 1:2 balsalavir azomethylpyrrolidone solvate xii.

The 1:2 baroxavir azomethylpyrrolidone solvate XII provided by the invention is characterized in that the XRPD pattern thereof has characteristic peaks at 2theta values of 8.66 +/-0.2 degrees, 9.06 +/-0.2 degrees, 10.04 +/-0.2 degrees, 10.70 +/-0.2 degrees, 20.00 +/-0.2 degrees, 20.50 +/-0.2 degrees, 21.50 +/-0.2 degrees, 22.52 +/-0.2 degrees, 23.42 +/-0.2 degrees, 24.58 +/-0.2 degrees, 25.64 +/-0.2 degrees, 29.12 +/-0.2 degrees and 31.66 +/-0.2 degrees.

Furthermore, the 1:2 baroxavir azomethine pyrrolidone solvate XII provided by the invention is further characterized in that the XRPD pattern also has characteristic peaks at 2theta values of 4.42 +/-0.2 degrees, 11.74 +/-0.2 degrees, 17.14 +/-0.2 degrees, 18.04 +/-0.2 degrees, 19.62 +/-0.2 degrees, 27.56 +/-0.2 degrees and 34.54 +/-0.2 degrees.

Further, the present invention provides a 1:2 balsalavir azomethylpyrrolidone solvate, XII, which is characterized in that the XRPD pattern substantially corresponds to that of FIG. 13.

Furthermore, the invention provides a 1:2 balsalavir azomethylpyrrolidone solvate XII which is characterized in that an endothermic peak appears when heated to a temperature of about 73.5 ℃ and 125.65 ℃, and the DSC/TGA chart thereof is substantially in accordance with that of FIG. 14.

It is another object of the invention to provide a process for the preparation of a 1:2 balsalavir azomethylpyrrolidone solvate, XII.

Further, the invention provides a preparation method of a 1:2 balosavir nitrogen methyl pyrrolidone solvate XII, which is characterized by comprising the following steps:

(1) adding the baroxavir solid to the N-methylpyrrolidone;

(2) heating to dissolve and clear;

(3) and (4) performing rotary evaporation and drying to obtain a solid, namely a solvate XII.

In the step (2), the dissolving temperature is preferably 60-70 ℃, and more preferably 65 ℃.

In the operation of the step (3), the rotary evaporation temperature is preferably 80-100 ℃.

The invention provides several new Barrosavir crystal forms and a preparation method thereof, and the obtained crystal forms have the advantages of good solubility, small hygroscopicity, stable process, strong operability, high yield, good reproducibility of preparation, stable crystal forms, suitability for medicine development and the like.

Drawings

Figures 1 and 2 provide XRPD and DSC diagrams, respectively, of crystalline balosavir form v.

Figures 3 and 4 provide XRPD and DSC/TGA plots, respectively, for crystalline form vii of baclovir.

Figures 5 and 6 provide XRPD and DSC/TGA plots, respectively, of crystalline form viii of baloxavir.

Figures 7 and 8 provide an XRPD pattern and DSC/TGA pattern, respectively, of crystalline form ix of baroxavir.

Figures 9 and 10 provide XRPD and DSC diagrams, respectively, of balosavir form x.

Figures 11 and 12 provide an XRPD pattern and a DSC pattern, respectively, of barcosivir form xi.

Figures 13 and 14 provide XRPD and DSC/TGA plots of 1:2 barcol oxavir azomethylpyrrolidone solvate, xii, respectively.

Detailed Description

The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the protection scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

In the examples below, unless otherwise indicated, the test procedures described are generally carried out according to conventional conditions or manufacturer's conditions; the raw materials and the reagents can be obtained by a commercially available mode.