CN114040908A

CN114040908A - Crystal form of factor XIa inhibitor and preparation method thereof

Info

Publication number: CN114040908A
Application number: CN202080042070.7A
Authority: CN
Inventors: 张�杰; 董吉川; 黄河; 雷鑫; 陈勇; 王仲清; 罗忠华; 黄芳芳
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2019-06-25
Filing date: 2020-06-17
Publication date: 2022-02-11
Also published as: WO2020259366A1

Abstract

A crystal form of a factor XIa inhibitor and a preparation method thereof, wherein an X-ray powder diffraction pattern of the crystal form comprises diffraction peaks with 2 theta angles of 6.9 +/-0.2 degrees, 15.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees. The crystal form has better performance and high stability, and can be used for preparing a medicinal preparation for treating cardiovascular diseases.

Description

Crystal form of factor XIa inhibitor and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a crystal form of a factor XIa inhibitor and a preparation method thereof.

Background

BMS-262084(CAS number: 253174-92-4), with the chemical name (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (diaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid, also referred to herein as compound (1), is a drug developed by BMS (Betamet-Shinobao) corporation for the treatment of cardiovascular diseases, which has the advantage of significantly reducing the risk of bleeding as an oral factor XIa inhibitor of thrombosis, and has the structure shown in formula (1):

patent application WO 9967215A1 discloses BMS-262084 compounds, but the solid substance obtained by the disclosed preparation process has a specific molecular formula C₁₈H ₃₁N ₇O ₅·1.56H ₂O, different from the water molecular weight of the crystalline and amorphous forms of BMS-262084 described herein.

A stereoselective synthesis of BMS-262084 an azetidinone-based tryptase inhibitor (literature source: Journal of Organic Chemistry,2002,67(11): 3595-. The inventor conducts experiments according to the disclosure of the document, and the experimental result obtains the crystal form A and the crystal form B, and the X-ray powder diffraction patterns of the crystal form A and the crystal form B are respectively shown in the figure 1 and the figure 2.

The crystal form of the medicine is an important factor influencing the quality of the medicine. Different crystal forms of the same medicament may have obvious difference in physicochemical properties such as appearance, fluidity, solubility, storage stability, bioavailability and the like, may have great difference, and may have different influences on storage transfer, application, stability, curative effect and the like of the medicament; in order to obtain a crystal form which is effective and beneficial to a pharmaceutical preparation, the crystallization behavior of the drug needs to be deeply explored so as to obtain the crystal form meeting the production requirement.

Disclosure of Invention

Summary of The Invention

The present invention provides novel crystalline forms of compound (1), and methods and compositions for their preparation.

The X-ray powder diffraction pattern of the crystal form comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 15.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees. The X-ray powder diffraction pattern of the crystal form comprises at least one peak or at least two peaks or three peaks in diffraction peaks with 2theta angles of 7.5 +/-0.2 degrees, 17.0 +/-0.2 degrees and 19.5 +/-0.2 degrees; or the crystalline form has an X-ray powder diffraction pattern that does not comprise at least one peak or at least two peaks or three peaks of the diffraction peaks having 2theta angles of 7.5 + -0.2 DEG, 17.0 + -0.2 DEG and 19.5 + -0.2 deg.

The differential scanning calorimetry curve of the crystal form has an endothermic peak at 122-126 ℃, or the differential scanning calorimetry curve of the crystal form has an endothermic peak at 128-132 ℃.

The crystal form is monohydrate or 1.5 hydrate. In some embodiments, the crystalline form is (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (dimethylaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid monohydrate. In some embodiments, the crystalline form is (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (dimethylaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid 1.5 hydrate.

In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.9 ± 0.2 °, 11.2 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 20.2 ± 0.2 °, 21.8 ± 0.2 °, 23.7 ± 0.2 ° and 28.2 ± 0.2 °. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.9 ± 0.2 °, 11.2 ± 0.2 °, 14.3 ± 0.2 °, 15.6 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 18.2 ± 0.2 °, 20.2 ± 0.2 °, 20.9 ± 0.2 °, 21.8 ± 0.2 °, 23.7 ± 0.2 ° and 28.2 ± 0.2 °. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.9 ± 0.2 °, 11.2 ± 0.2 °, 13.9 ± 0.2 °, 14.3 ± 0.2 °, 15.6 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 18.2 ± 0.2 °, 18.8 ± 0.2 °, 20.2 ± 0.2 °, 20.9 ± 0.2 °, 21.8 ± 0.2 °, 22.4 ± 0.2 °, 23.7 ± 0.2 °, 27.4 ± 0.2 °, 28.2 ± 0.2 °, 29.4 ± 0.2 °, 32.3 ± 0.2 °, 35.1 ± 0.2 ° and 36.3 ± 0.2 °.

The crystal form provided by the invention has better performance and high stability, and can be used for preparing a medicinal preparation for treating cardiovascular diseases.

A method of making the crystalline form, comprising: dissolving or suspending a raw material compound (1) (BMS-262084) in a solvent, wherein a solution formed by complete dissolution is volatilized and dried to obtain the crystal form; and suspending, filtering and drying the solid-liquid mixture which is not completely dissolved to obtain the crystal form.

The present invention also provides a composition comprising the crystalline form of compound (1) as described above. The crystal form is at least 90% of the compound (1) according to the mass ratio, or the crystal form is not more than 0.5% -5% of the compound (1).

Definition of terms

The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

The term "crystal form" is used to describe the state of existence of a solid compound, describing the collection of various parameters of ionic, atomic or molecular composition, symmetry properties and periodic arrangement rules within the crystal.

The term "relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strong peak in a set of diffraction peaks assigned to a certain crystal form, when the intensity of the first strong peak is defined as 100%.

The term "substantially as shown" means that at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the figure.

In the context of the present invention, the 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).

The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not ascribe to background noise.

The crystalline form has an X-ray powder diffraction peak whose measure of the 2theta or diffraction peak of the X-ray powder diffraction pattern has experimental error which may differ slightly between one machine and another and between one sample and another, the value of the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units, and thus the value of the 2theta or diffraction peak cannot be considered absolute.

The Differential Scanning Calorimetry (DSC) curve of the crystal form has experimental errors, the position and peak value of the endothermic peak may slightly differ between one machine and another machine and between one sample and another sample, and the numerical value of the experimental errors or differences may be 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

The thermogravimetric analysis (TGA) of the crystalline form has experimental errors, the temperature and amount of weight loss may differ slightly between one machine and another and between one sample and another, and the experimental error or difference may have a value of about +/-0.1 units, about +/-0.05 units, or about +/-0.01 units, so the values of the temperature and amount of weight loss cannot be considered absolute.

In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may differ by 1%, 2%, or 5%.

By "room temperature" is meant a temperature of about 15 ℃ to 32 ℃ or about 20 ℃ to 30 ℃ or about 23 ℃ to 28 ℃ or about 28 ℃.

By "elevated temperature" is meant a temperature of from about 40 ℃ to 100 ℃ or from about 50 ℃ to 70 ℃ or about 60 ℃.

In the present invention, when the solid is dried, the solid is dried to a constant weight.

Detailed Description

The inventors have developed a crystalline form of compound (1) and a process for producing the same through research.

In a first aspect, a novel crystalline form of compound (1) has unexpectedly been discovered during the present study, said crystalline form having an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.9 ± 0.2 °, 15.9 ± 0.2 °, 21.8 ± 0.2 °, 23.7 ± 0.2 ° and 28.2 ± 0.2 °.

The crystal form of the compound (1), namely the new crystal form, including the crystal form I or the crystal form II, has good performance, high solubility and high bioavailability; or/and good in stability, is beneficial to storage, thereby meeting the requirement of drug stability; the hydroscopic property is low, or/and have good performance in the aspect of static electricity, the static electricity is low, help to operate in the production technology; and as an oral factor XIa inhibitor for thrombosis, has the effect of reducing the risk of bleeding.

A crystalline form of compound (1) having the following properties: the X-ray powder diffraction pattern thereof contains diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 15.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern of the crystal form comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern of the crystal form comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.0 +/-0.2 degrees, 19.5 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.5 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 27.4 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 27.4 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.4 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.4 +/-0.2 degrees, 27.4 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.

In some embodiments, the crystalline form of compound (1) has the following properties: an X-ray powder diffraction pattern thereof does not include at least one of peaks having 2theta angles of 7.5 + -0.2 DEG, 17.0 + -0.2 DEG and 19.5 + -0.2 deg. In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern thereof does not contain peaks at 2theta angles of 7.5 + -0.2 DEG, 17.0 + -0.2 DEG and 19.5 + -0.2 deg.

In some embodiments, the crystalline form of compound (1) has the following properties: an X-ray powder diffraction pattern thereof contains at least one of peaks having 2theta angles of 7.5 + -0.2 DEG, 17.0 + -0.2 DEG and 19.5 + -0.2 deg. In some embodiments, the crystalline form of compound (1) has the following properties: the X-ray powder diffraction pattern thereof contains peaks at 2theta angles of 7.5 + -0.2 deg., 17.0 + -0.2 deg. and 19.5 + -0.2 deg..

In the present application, a crystalline form of compound (1) which does not contain at least one diffraction peak among 7.5 ± 0.2 °, 17.0 ± 0.2 °, 19.5 ± 0.2 °, in X-ray powder diffraction pattern 2 θ angle is referred to as "crystalline form I"; otherwise, it is called "form II".

In some embodiments, form I of compound (1) has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.9 ± 0.2 °, 15.9 ± 0.2 °, 21.8 ± 0.2 °, 23.7 ± 0.2 ° and 28.2 ± 0.2 °; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 27.4 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.

In some embodiments, form I of compound (1) does not comprise at least one peak or at least two peaks or three peaks in the diffraction peaks at 2 Θ angles of 7.5 ± 0.2 °, 17.0 ± 0.2 °, and 19.5 ± 0.2 °.

In some embodiments, form I of compound (1) does not comprise at least one peak or at least two peaks or three peaks in the diffraction peaks at 2 Θ angles of 7.5 ± 0.2 °, 17.0 ± 0.2 °, and 19.5 ± 0.2 ° in its X-ray powder diffraction pattern; and: the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 15.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 27.4 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.

In some embodiments, form I of compound (1) has an X-ray powder diffraction pattern substantially as shown in figure 3, wherein the relative intensity of the peak at diffraction angle 2 Θ of 15.9 ± 0.2 ° degrees is greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

In some embodiments, form ii of compound (1) has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks or three peaks of diffraction peaks having 2 Θ angles of 7.5 ± 0.2 °, 17.0 ± 0.2 °, and 19.5 ± 0.2 °.

In some embodiments, form ii of compound (1) has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks or three peaks of diffraction peaks having 2 Θ angles of 7.5 ± 0.2 °, 17.0 ± 0.2 °, and 19.5 ± 0.2 °; and the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 7.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.

In some embodiments, the form ii of compound (1) has an X-ray powder diffraction pattern substantially as shown in fig. 7, wherein the relative intensity of the peak at diffraction angle 2 Θ of 15.9 ± 0.2 ° degrees is greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

The crystal form of the compound (1) also has the following characteristics: the Differential Scanning Calorimetry (DSC) has an endothermic peak at 75-175 ℃.

In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of form I of compound (1) has an endothermic peak at 100 ℃ to 140 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of form I of compound (1) has an endothermic peak at 120 ℃ to 128 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of form I of compound (1) has an endothermic peak at 122 ℃ to 126 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of form I of compound (1) has an endothermic peak at 122 ℃ to 126 ℃ with an endothermic peak top of 124 ℃. In some embodiments, a Differential Scanning Calorimetry (DSC) curve of form i of compound (1) is shown in figure 4.

In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of form ii of compound (1) has an endothermic peak at 110 ℃ to 150 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of form ii of compound (1) has an endothermic peak at 126 ℃ to 134 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of form ii of compound (1) has an endothermic peak at 128 ℃ -132 ℃. In a specific embodiment, the Differential Scanning Calorimetry (DSC) curve of form ii of compound (1) has an endothermic peak at 128 ℃ to 132 ℃ with a peak top of the endothermic peak at 130 ℃. In some embodiments, a Differential Scanning Calorimetry (DSC) curve of form ii of compound (1) is shown in figure 8.

The crystal form of the compound (1) also has the following characteristics: the thermogravimetric analysis curve (TGA) of the crystalline form of compound (1) shows that the crystalline form i of compound (1) has a weight loss of about 3.5% to 7.5% at 30 ℃ to 150 ℃.

In a specific embodiment, the thermogravimetric analysis curve (TGA) of form I of compound (1) shows a weight loss of about 4.0% at 30 ℃ to 150 ℃. In a specific embodiment, the thermogravimetric analysis plot (TGA) of crystalline form I of compound (1) is shown in figure 5.

In a specific embodiment, the thermogravimetric analysis (TGA) of form ii of compound (1) shows a weight loss of about 6.0% at 30 ℃ to 150 ℃. In a specific embodiment, the thermogravimetric analysis (TGA) of form ii of compound (1) is shown in figure 9.

In some embodiments, the crystalline form of compound (1) is an hydrate or hydrate. In some embodiments, the crystalline form of compound (1) has a water content of about 4.0%. In some embodiments, the crystalline form of compound (1) has a water content of about 6.0%.

In some embodiments, the crystalline form of compound (1) is a monohydrate. In some embodiments, the crystalline form of compound (1) is 1.5 hydrate. In some embodiments, the crystalline form is (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (dimethylaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid monohydrate. In some embodiments, the crystalline form is (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (dimethylaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid and 1.5 hydrate.

In some embodiments, the crystalline form I of compound (1) is an hydrate or hydrate. In some embodiments, the compound (1) has a form I water content of about 4.0%. In some embodiments, the crystalline form I of compound (1) is a monohydrate.

In some embodiments, the compound (1) has a form ii water content of about 6.0%. In some embodiments, the crystalline form ii of compound (1) is 1.5 hydrate.

In a particular embodiment, the crystalline form I of compound (1) also has the following properties: the dynamic adsorption equilibrium curve of the product has the advantages that the moisture absorption of the product is larger along with the increase of the humidity, and when the humidity reaches 95.0%, the moisture absorption amount is 1.6%, namely the moisture is increased by 1.6%. In a particular embodiment, said crystalline form I of compound (1) further has the following properties: the dynamic moisture sorption instrument (DVS) isotherm diagram is shown in fig. 6. In one embodiment, the crystalline form ii of compound (1) further has the following properties: the dynamic adsorption equilibrium curve has the advantages that the moisture absorption of the product is larger along with the increase of the humidity, and when the humidity reaches 95.0%, the moisture absorption moisture content of the crystal form II is 5.7%, namely the moisture gain is 5.7%. In a particular embodiment, said crystalline form ii of compound (1), further has the following characteristics: the dynamic moisture content adsorption apparatus (DVS) isotherm diagram is shown in fig. 10.

In some embodiments, form I of compound (1), further has the following properties: the aforementioned form I is at least 90%, alternatively at least 95%, of compound (1). In some embodiments, the aforementioned form I is at least 98% or at least 99% of compound (1).

In some embodiments, form ii of compound (1) further has the following properties: the aforementioned form ii is at least 90%, or at least 95% of compound (1). In some embodiments, the aforementioned form ii is at least 98% or at least 99% of compound (1).

According to some embodiments of the invention, the crystal form I has good stability and fluidity and low hygroscopicity, is beneficial to material transfer in a production process, is beneficial to use and stability of raw materials in a pharmaceutical preparation, and is beneficial to preparation and quality stability of the pharmaceutical preparation.

According to some embodiments of the invention, the crystal form II has better stability and flowability and relatively lower hygroscopicity, and can be used for preparing pharmaceutical preparations.

In a second aspect, the present invention provides a process for the preparation of said crystalline form of compound (1).

The preparation method of the crystal form of the compound (1) is simple, convenient to operate, mild in condition, high in yield and purity, and suitable for industrial production.

A method for preparing a crystalline form of the compound (1) comprises: dissolving or suspending a raw material compound (1) (BMS-262084) in a solvent, wherein a solution formed by complete dissolution is volatilized and dried to constant weight to obtain the crystal form; and suspending the solid-liquid mixture which is not completely dissolved, filtering and drying to constant weight to obtain the crystal form. In some embodiments, a method of preparing a crystalline form of the compound (1) comprises: dissolving or suspending a raw material compound (1) (BMS-262084) in a solvent, wherein a solution formed by complete dissolution is volatilized and dried to constant weight to obtain the crystal form; suspending the solid-liquid mixture which is not completely dissolved, filtering and drying the solid-liquid mixture to constant weight to obtain the crystal form; the solvent includes at least one selected from the group consisting of water, isopropanol, n-propanol, methanol, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane.

In some embodiments, a method of preparing a crystalline form of the compound (1) comprises: dissolving the raw material compound (1) (BMS-262084) in isopropanol, n-propanol, methanol, dioxane or a mixed solvent of isopropanol, n-propanol, methanol and dioxane and water, volatilizing a solution formed by complete dissolution at room temperature, and drying to obtain the crystal form. In some embodiments, a method of making a crystalline form of the compound (1) comprises: suspending the raw material compound (1) (BMS-262084) in water, ethylene glycol dimethyl ether, tetrahydrofuran or a mixed solvent thereof to form a solid-liquid mixture, suspending the solid-liquid mixture at room temperature, filtering and drying to obtain the crystal form.

In some embodiments, a method of preparing a crystalline form of the compound (1) comprises: dissolving or suspending a raw material compound (1) (BMS-262084) in a solvent, wherein a solution formed by complete dissolution is volatilized and dried to constant weight to obtain the crystal form; suspending the solid-liquid mixture which is not completely dissolved, filtering and drying the solid-liquid mixture to constant weight to obtain the crystal form; the solvent is selected from at least one of water, isopropanol, glycol dimethyl ether and tetrahydrofuran; the crystal form is a crystal form I.

In a specific embodiment, a process for preparing the crystalline form I of the compound (1) comprises: dissolving the raw material compound (1) in a mixed solvent of isopropanol and water, completely dissolving the solution at room temperature to form a solution, and volatilizing and drying the solution to obtain the crystal form I.

In a specific embodiment, a process for preparing the crystalline form I of the compound (1) comprises: and (2) suspending the raw material compound (1) in water at high temperature to form a mixed solution, suspending the mixed solution at high temperature or room temperature, filtering, and drying to obtain the crystal form I.

In some embodiments, a method of preparing the crystalline form I of the compound (1) comprises: suspending the raw material compound (1) in a mixed solvent of ethylene glycol dimethyl ether and water or a mixed solvent of tetrahydrofuran and water to form a solid-liquid mixture, suspending the solid-liquid mixture at room temperature, filtering and drying to obtain the crystal form I. In some embodiments, a method of preparing the crystalline form I of the compound (1) comprises: suspending the raw material compound (1) in a mixed solvent of ethylene glycol dimethyl ether and water or a mixed solvent of tetrahydrofuran and water at room temperature to form a solid-liquid mixture, suspending the solid-liquid mixture at room temperature, filtering and drying to obtain the crystal form I.

In some embodiments, a method of preparing a crystalline form of the compound (1) comprises: dissolving or suspending a raw material compound (1) (BMS-262084) in a solvent, wherein a solution formed by complete dissolution is volatilized and dried to constant weight to obtain the crystal form; suspending the solid-liquid mixture which is not completely dissolved, filtering and drying the solid-liquid mixture to constant weight to obtain the crystal form; the solvent is at least one selected from water, n-propanol, methanol and dioxane; the crystal form is a crystal form II.

In a specific embodiment, a process for preparing the crystalline form ii of the compound (1) comprises: dissolving the raw material compound (1) in n-propanol, methanol or dioxane at room temperature or in a mixed solvent of the n-propanol, the methanol or dioxane and water, completely dissolving the solution at room temperature, volatilizing, and drying to obtain the crystal form II.

In a specific embodiment, a process for preparing the crystalline form ii of the compound (1) comprises: and (2) suspending the raw material compound (1) in water at room temperature to form a solid-liquid mixture, suspending the solid-liquid mixture at room temperature, filtering and drying to obtain the crystal form II.

In the method for preparing the crystal form, the suspension time can be 4 hours to 120 hours, or 4 hours to 96 hours, or 4 hours to 72 hours, or 4 hours to 36 hours, or 24 hours to 48 hours, or 36 hours to 72 hours, or 8 hours to 36 hours, or 12 hours to 24 hours.

In some embodiments, the method of making the crystalline form comprises suspending for no more than 48 hours to provide form I.

In some embodiments, the method of making the crystalline form is performed for a suspension time of not less than 48 hours to obtain form ii.

In another aspect, the present invention also provides a composition comprising the crystalline form of compound (1) as described above.

The crystal form is at least 90% of the compound (1) according to the mass ratio, or the crystal form is not more than 0.5% -5% of the compound (1).

In some embodiments, the composition comprises a crystalline form of the aforementioned compound (1), wherein the crystalline form is at least 90% of the compound (1) by mass ratio. In some embodiments, the composition comprises a crystalline form of the aforementioned compound (1), wherein the crystalline form is at least 95% or at least 99% of the compound (1), on a mass ratio basis. In some embodiments, the composition comprises a crystalline form of the aforementioned compound (1), wherein the crystalline form is at least 0.5% to 5% of the compound (1) by mass ratio. In some embodiments, a composition comprises a crystalline form of the aforementioned compound (1), wherein the crystalline form is at least 5% of compound (1), by mass. In some embodiments, the composition comprises the crystal form of the compound (1), wherein the crystal form is not more than 0.5-5% of the compound (1). In some embodiments, the composition comprises a crystalline form of the aforementioned compound (1), wherein the crystalline form is not more than 5% of the compound (1) by mass.

In some embodiments, a composition comprises a crystalline form of the aforementioned compound (1), said crystalline form being form I and/or form ii. In some embodiments, a composition comprises form I and/or form ii of the aforementioned compound (1).

In some embodiments, a composition comprises form I of the aforementioned compound (1), wherein form I is at least 90% of compound (1), on a mass ratio basis. In some embodiments, a composition comprises form I of the aforementioned compound (1), wherein form I is at least 95%, or at least 99% of compound (1), on a mass ratio basis. In some embodiments, a composition comprises the aforementioned form I of compound (1), wherein form I is at least 0.5% to 5% of compound (1), by mass ratio. In some embodiments, a composition comprises form I of the aforementioned compound (1), wherein form I is at least 5% of compound (1), on a mass ratio basis. In some embodiments, a composition comprises the aforementioned form I of compound (1), wherein form I is not more than 0.5% to 5% of compound (1) by mass. In some embodiments, a composition comprises form I of the aforementioned compound (1), wherein form I is not more than 5% of compound (1), by mass.

In some embodiments, a composition comprises form ii of the aforementioned compound (1), wherein form ii is at least 90% of compound (1), on a mass ratio basis. In some embodiments, a composition comprises form ii of the aforementioned compound (1), wherein form ii is at least 95%, or at least 99% of compound (1), on a mass basis. In some embodiments, a composition comprises the aforementioned compound (1) in the form of crystal form ii, wherein the form ii is at least 0.5% to 5% of the compound (1). In some embodiments, a composition comprises form ii of the aforementioned compound (1), wherein form ii is at least 5% of compound (1), on a mass basis. In some embodiments, a composition comprises the aforementioned compound (1) in a crystal form ii, wherein the crystal form ii is not more than 0.5% to 5% of the compound (1). In some embodiments, a composition comprises form ii of the aforementioned compound (1), wherein form ii is no more than 5% of compound (1), by mass.

The composition can also comprise pharmaceutically acceptable auxiliary materials or carriers, such as fillers, diluents, lubricants and the like. In some embodiments, the composition further comprises a pharmaceutically acceptable adjuvant or carrier, including a lubricant. In some embodiments, the lubricant is magnesium stearate.

The composition can be prepared into any suitable pharmaceutical preparation, such as tablets, capsules, granules, suspensions, injections and the like.

Drawings

Figure 1 shows an X-ray powder diffraction pattern (XRPD) of compound (1) form a;

figure 2 shows an X-ray powder diffraction pattern (XRPD) of compound (1) form B;

figure 3 shows an X-ray powder diffraction pattern (XRPD) of compound (1) form I;

figure 4 shows a Differential Scanning Calorimetry (DSC) profile of compound (1) form I;

figure 5 shows a thermogravimetric analysis plot (TGA) of compound (1) form I;

FIG. 6 shows a dynamic moisture sorption instrument (DVS) isotherm diagram of form I of Compound (1);

FIG. 7 shows an X-ray powder diffraction pattern (XRPD) of Compound (1) form II;

FIG. 8 shows a Differential Scanning Calorimetry (DSC) profile of Compound (1) form II;

FIG. 9 shows a thermogravimetric analysis plot (TGA) of Compound (1) form II;

FIG. 10 shows a dynamic moisture sorption instrument (DVS) isotherm diagram of form II of compound (1);

FIG. 11 shows the amorphous X-ray powder diffraction pattern (XRPD) of Compound (1);

FIG. 12 shows the isotherm diagram of the amorphous dynamic moisture sorption instrument (DVS) for Compound (1).

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.

The reagents used in the present invention are either commercially available or can be prepared by methods known in the art or by methods described herein.

In the present invention, DEG C means centigrade, mg means milligram, mL means milliliter, h means hour, and mm means millimeter.

In the invention, the hydrate is calculated according to the molar ratio, and the molar ratio of (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (diaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid to water in the monohydrate is 1: 1; 1.5 molar ratio of (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (diaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid to water in water 1: 1.5.

Parameters of the instrument

All analyses below were performed at room temperature unless otherwise specified in the parameters.

X-ray powder diffraction (XRPD)

X-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer in the netherlands equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. The radiation source used was a source of radiation of (Cu, k α,

1.540598；

1.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50) with the voltage set at 45KV and the current set at 40 ma.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 10mm, with a theta-theta continuous scanning mode, yielding an effective 2theta range of 3 deg. -60 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample by using a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample was scanned at a scan step of 0.0167 ° in the range of 3-60 ° 2 θ ± 0.2 ° to produce a conventional XRPD pattern. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the ordinate is diffraction intensity expressed in counts (counts), and the abscissa is diffraction angle 2 θ expressed in degrees (°).

Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter Q2000. The sample (about 1mg to 3mg) was placed in an aluminum pan and the weight was accurately recorded. The pan was covered with a lid and then crimped and the sample was transferred to the instrument for measurement. The sample cell was equilibrated at 30 deg.C and heated to a final temperature of 300 deg.C at a rate of 50 deg.C/min under a nitrogen purge. In the DSC chart, the abscissa represents Temperature (DEG C) and the ordinate represents the Heat Flow (W/g) released per unit mass of a substance.

Thermogravimetric analysis (TGA)

Thermogravimetric analysis was performed using a thermogravimetric analyzer Q500, placing the appropriate amount of sample in a platinum sample pan, and heating at a rate of 60 ℃/min under nitrogen atmosphere, with a temperature range of 30 to 300 ℃. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents mass percent (Weight%).

Dynamic vapor sorption analyzer DVS

A DVS test isothermal adsorption equilibrium curve test method comprises the following steps: DVS-intransics, at 25.0 ℃, starts at 0% relative humidity with a change in relative humidity (0% -95.0% -0%), reaches 95% relative humidity in 5% relative humidity steps, and then reaches 0% relative humidity again in 5% relative humidity steps. When the absolute value of the change dm/dt in the weight of the sample per unit time under a certain relative humidity condition is less than 0.5%, the sample is considered to reach the equilibrium, and then the next relative humidity is entered. Detecting the variation of hygroscopicity of the product under the (0% -95.0% -0%) relative humidity circulation condition.

Example 1

Only ethanol solvents are mentioned in the A stereoselective synthesis of BMS-262084 an azetidinone-based tryptase inhibitor (literature source: Journal of Organic Chemistry,2002,67(11): 3595-. Since the crystallization purification process was not specifically provided, only a part of the experiment was performed using an ethanol solvent.

1) Room temperature volatilization of ethanol solvent: 50mg of BMS-262084 (amorphous) was added to 1.0mL of ethanol solvent and completely dissolved at room temperature (about 25 ℃). The crystal form condition of the obtained solid product is detected to be crystal form A after being opened for volatilizing for two days at room temperature, and the crystal form A is shown in figure 1 and is considered to contain a small amount of amorphous; but it is unstable and undergoes crystal transformation at room temperature, and after one day at room temperature, XRPD was detected and found to transform to a mixture containing form a, other forms and amorphous form.

2) High-temperature volatilization of ethanol solvent: adding 50mg BMS-262084 into 1.0mL ethanol solvent, dissolving completely at high temperature (about 60 ℃), volatilizing at high temperature to obtain solid product, and detecting the crystal form condition to obtain crystal form B (containing a large amount of amorphous form), as shown in figure 2.

Example 2

Adding 50.0mg BMS-262084 and 1.0mL purified water into a 5mL EP tube, magnetically stirring at 200rpm, stirring the solid-liquid mixture at a high temperature (about 60.0 ℃) for about 24 hours until the solid-liquid mixture is still insoluble, stopping heating, keeping stirring, naturally cooling to room temperature (about 28 ℃), stirring at room temperature for about 1 day, filtering, drying at 50 ℃ in vacuum for 24 hours to obtain about 20.0mg of white solid, and carrying out solid analysis detection to obtain the crystal form I, wherein the crystal form I is shown in figures 3 to 6.

Examples 2 to 02

50.0mg of BMS-262084 and 1.0mL of purified water were added to a 5mL EP tube, and the solution was not completely dissolved at high temperature (about 60.0 ℃) by magnetic stirring at 200 rpm. Suspending the solid-liquid mixture at high temperature (about 60 deg.C) under magnetic stirring at 200rpm for about 1 day, filtering at high temperature, vacuum drying at 50 deg.C for 24 hr to obtain white solid of about 20.0mg, and performing solid analysis to obtain crystal form I, which is consistent with fig. 3-6.

Example 3

Adding 100.0mg BMS-262084 and 1.0mL purified water into a 5mL EP tube, magnetically stirring at 200rpm, stirring the solid-liquid mixture at a high temperature (about 60.0 ℃) for about 24 hours until the solid-liquid mixture is still insoluble, stopping heating, keeping stirring, naturally cooling to room temperature (about 28 ℃), stirring at room temperature for about 1 day, filtering, drying at 50 ℃ in vacuum for 24 hours to obtain about 55.0mg of white solid, and carrying out solid analysis detection to obtain a crystal form I which is consistent with the crystal form I in the images 3 to 6.

Examples 3 to 02

A5 mL EP tube was charged with 100.0mg of BMS-262084 and 1.0mL of purified water, and was magnetically stirred at 200rpm, and failed to completely dissolve at high temperature (about 60.0 ℃). Suspending the solid-liquid mixture at high temperature (about 60 deg.C) under magnetic stirring at 200rpm for about 1 day, filtering at high temperature, vacuum drying at 50 deg.C for 24 hr to obtain white solid of about 55.0mg, and performing solid analysis to obtain crystal form I, which is consistent with fig. 3-6.

Example 4

Adding 200.0mg BMS-262084 and 2.0mL purified water into a 5mL EP tube, magnetically stirring at 200rpm, stirring the solid-liquid mixture at a high temperature (about 60.0 ℃) for about 24 hours until the solid-liquid mixture is still insoluble, stopping heating, keeping stirring, naturally cooling to room temperature (about 28 ℃), stirring at room temperature for about 3 days, filtering, drying at 50 ℃ in vacuum for 24 hours to obtain about 105mg of white solid, and carrying out solid analysis detection to obtain a crystal form I which is consistent with the crystal form I in the images 3 to 6.

Examples 4 to 02

To a 5mL EP tube, 200.0mg of BMS-262084 and 2.0mL of purified water were added, and the mixture was magnetically stirred at 200rpm and failed to be completely dissolved at a high temperature (about 60.0 ℃). Suspending the solid-liquid mixture at high temperature (about 60 deg.C) under magnetic stirring at 200rpm for about 1 day, filtering at high temperature, vacuum drying at 50 deg.C for 24 hr to obtain white solid of about 105mg, and performing solid analysis to obtain crystal form I consistent with fig. 3-6.

Example 5

50.0mg of BMS-262084 and 1.0mL of purified water were added to a 5mL EP tube, and the mixture was magnetically stirred at 200rpm and was not completely dissolved at room temperature (about 28.0 ℃). Suspending the solid-liquid mixture at room temperature (about 28.0 ℃) under the condition of magnetic stirring at 200rpm for about 3 days, filtering, drying at 50 ℃ in vacuum for 24 hours to obtain white solid of about 25.0mg, and carrying out solid state analysis and detection to obtain the crystal form II, wherein the crystal form II is shown in figures 7 to 10.

Example 6

A5 mL EP tube was charged with 100.0mg of BMS-262084 and 1.0mL of purified water, and was magnetically stirred at 200rpm, failing to completely dissolve at room temperature (about 28.0 ℃). Suspending the solid-liquid mixture at room temperature (about 28.0 deg.C) under magnetic stirring at 200rpm for about 3 days, filtering, vacuum drying at 50 deg.C for 24 hr to obtain white solid of about 65.0mg, and performing solid analysis to obtain crystal form II, which is consistent with FIG. 7-FIG. 10.

Example 7

To a 5mL EP tube, 200.0mg of BMS-262084 and 2.0mL of purified water were added, and the mixture was magnetically stirred at 200rpm and was not completely dissolved at room temperature (about 28.0 ℃). Suspending the solid-liquid mixture at room temperature (about 28.0 deg.C) under magnetic stirring at 200rpm for about 3 days, filtering, vacuum drying at 50 deg.C for 24 hr to obtain white solid of about 135mg, and performing solid state analysis to obtain crystal form II, which is consistent with FIG. 7-FIG. 10.

Example 8

A50 mL flask was charged with 2.00g of BMS-262084 and 50.0mL of methanol solvent, and was magnetically stirred at 200rpm to completely dissolve at room temperature (about 28.0 ℃). Removing solvent from the solution by rotary evaporation, vacuum drying at 50 deg.C for 24 hr to obtain white solid about 1.90g, and performing solid state analysis to determine amorphous form, see FIG. 11 and FIG. 12.

Example 9

A5 mL EP tube was charged with 30mg BMS-262084 (amorphous), 0.5mL organic solvent and 0.5mL purified water, and magnetically stirred for 2 hours at 200 rpm. Wherein the solution formed by complete dissolution is screened in a room temperature volatilization mode, the solid-liquid mixture which is not completely dissolved is screened in a room temperature suspension mode, and the suspension and volatilization time is three days; and finally, filtering, and carrying out solid state analysis detection on the obtained solid, wherein the result is shown in table 1.

TABLE 1

Note: y: indicates complete dissolution; n: indicating incomplete dissolution.

Example 10

High-temperature test: taking BMS-262084 crystal forms I and II and an appropriate amount of amorphous samples, respectively, laying the samples in a weighing bottle, placing the samples in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH75 +/-5%, then taking about 10mg of the samples in 5, 10 and 15 days, respectively, and testing the X-ray powder diffraction pattern.

High humidity test: taking BMS-262084 crystal forms I and II and an appropriate amount of amorphous samples, respectively, laying the samples in a weighing bottle, placing the samples in a constant temperature and humidity box with the temperature of 25 ℃ and the RH of 92.5 +/-5 percent, then taking about 10mg of the samples in 5, 10 and 15 days, respectively, and testing the X-ray powder diffraction pattern.

And (3) illumination test: taking BMS-262084 crystal forms I and II and an appropriate amount of amorphous samples respectively, flatly spreading the samples into a weighing bottle, placing the samples in a constant temperature and humidity box (25 ℃, RH60 +/-5%) with visible light 4500Lux +/-500 Lux and ultraviolet light 1.7W X h/m2, then taking about 10mg of the samples respectively in 5, 10 and 15 days, and testing the X-ray powder diffraction pattern.

Test results show that the X-ray powder diffraction patterns of the crystal form I and the crystal form II are respectively consistent with the patterns shown in figures 3 and 7. The crystal form I and the crystal form II are stable under the conditions of high temperature, high humidity and illumination, and the crystal forms are not changed. The X-ray powder diffraction pattern of the amorphous form is consistent with that shown in figure 7 under high temperature and high humidity conditions, but the X-ray powder diffraction pattern of the amorphous form is consistent with that shown in figure 11 under illumination conditions, and the amorphous form is stable only under illumination conditions and is converted into a crystal form II under high temperature and high humidity conditions.

Example 11

Taking BMS-262084 crystal forms I and II and amorphous sample, respectively, testing their hygroscopicity, and testing their dynamic adsorption equilibrium curves by DVS (model: DVS-INTRINSIC), respectively, see FIG. 6, FIG. 10, and FIG. 12. The variation range of the humidity (0-95.0%) at 25.0 ℃ is that the hygroscopicity of the product is higher along with the increase of the humidity. When the humidity reaches 95.0%, the moisture absorption content of BMS-262084 crystal form I is only about 1.6% at least; the moisture absorption content of the crystal form II is about 5.7 percent; the moisture absorption content of the amorphous form was about 12.0%. Compared with the amorphous form, the crystal form of the invention has obviously lower hygroscopicity, especially the crystal form I.

While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims

A crystalline form of the compound (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (dimethylaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid having an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 6.9 ± 0.2 °, 15.9 ± 0.2 °, 21.8 ± 0.2 °, 23.7 ± 0.2 ° and 28.2 ± 0.2 °.
The crystalline form of claim 1, wherein an X-ray powder diffraction pattern of the crystalline form comprises diffraction peaks at 2 Θ angles of 6.9 ± 0.2 °, 11.2 ± 0.2 °, 15.9 ± 0.2 °, 17.5 ± 0.2 °, 20.2 ± 0.2 °, 21.8 ± 0.2 °, 23.7 ± 0.2 ° and 28.2 ± 0.2 °; or the X-ray powder diffraction pattern of the crystal form comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 23.7 +/-0.2 degrees and 28.2 +/-0.2 degrees; or the X-ray powder diffraction pattern of the crystal form comprises diffraction peaks with 2theta angles of 6.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.6 +/-0.2 degrees, 15.9 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.9 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.7 +/-0.2 degrees, 27.4 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.4 +/-0.2 degrees, 32.3 +/-0.2 degrees, 35.1 +/-0.2 degrees and 36.3 +/-0.2 degrees.
The crystalline form of claim 1 or 2, which is a monohydrate or a 1.5 hydrate.
The crystalline form of any of claims 1-3, wherein the crystalline form has a differential scanning calorimetry curve with an endothermic peak at 122 ℃ to 126 ℃ or an endothermic peak at 128 ℃ to 132 ℃.
The crystalline form of any one of claims 1-4 having an X-ray powder diffraction pattern comprising at least one peak or at least two peaks or three peaks of diffraction peaks having 2 θ angles of 7.5 ± 0.2 °, 17.0 ± 0.2 ° and 19.5 ± 0.2 °; or the crystalline form has an X-ray powder diffraction pattern that does not comprise at least one peak or at least two peaks or three peaks of the diffraction peaks having 2theta angles of 7.5 + -0.2 DEG, 17.0 + -0.2 DEG and 19.5 + -0.2 deg.
The crystalline form of any one of claims 1-5, wherein the crystalline form has an X-ray powder diffraction pattern substantially as shown in figure 3, or the crystalline form has an X-ray powder diffraction pattern substantially as shown in figure 7.
The crystalline form of any one of claims 1-4 having an X-ray powder diffraction pattern that does not comprise at least one peak or at least two peaks or three peaks of the diffraction peaks having 2 θ angles of 7.5 ± 0.2 °, 17.0 ± 0.2 ° and 19.5 ± 0.2 °.
A method of preparing the crystalline form of any one of claims 1-7, comprising: dissolving or suspending the raw materials in a solvent, wherein the solution formed by complete dissolution is volatilized and dried to constant weight to obtain the crystal form; suspending the solid-liquid mixture which is not completely dissolved, filtering and drying the solid-liquid mixture to constant weight to obtain the crystal form; the solvent includes at least one selected from the group consisting of water, isopropanol, n-propanol, methanol, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane.
The method of claim 8, comprising: dissolving the raw materials in a mixed solvent of isopropanol and water, completely dissolving the raw materials at room temperature to form a solution, and volatilizing and drying the solution to obtain the crystal form; or suspending the raw materials in water at high temperature to form a mixed solution, suspending the mixed solution at high temperature or room temperature, filtering, and drying to obtain the crystal form; or suspending the raw material in a mixed solvent of ethylene glycol dimethyl ether and water or a mixed solvent of tetrahydrofuran and water at room temperature to form a solid-liquid mixture, suspending the solid-liquid mixture at room temperature, filtering and drying to obtain the crystal form.
The method of claim 8, comprising: dissolving the raw materials in n-propanol, methanol or dioxane at room temperature, or in a mixed solvent of n-propanol, methanol or dioxane and water, completely dissolving the raw materials at room temperature to form a solution, and volatilizing and drying the solution to obtain the crystal form; or suspending the raw materials in water at room temperature to form a solid-liquid mixture, suspending the solid-liquid mixture at room temperature, filtering and drying to obtain the crystal form.
A composition comprising the crystalline form of any one of claims 1-7 and a pharmaceutically acceptable adjuvant or carrier; wherein the crystal form is at least 90% of the compound (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (diaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid or the crystal form is not more than 0.5% -5% of the compound (2S,3R) -1- [4- (tert-butylcarbamoyl) piperazine-1-carbonyl ] -3- [3- (diaminomethylamino) propyl ] -4-cyclopropylamide-2-carboxylic acid, in terms of mass ratio.
The composition of claim 11, wherein the crystalline form has an X-ray powder diffraction pattern that does not comprise at least one peak or at least two peaks or three peaks of the diffraction peaks having 2 Θ angles of 7.5 ± 0.2 °, 17.0 ± 0.2 ° and 19.5 ± 0.2 °.