CN112390812A

CN112390812A - Crystalline and amorphous solids of Ruogeli compounds and methods of making the same

Info

Publication number: CN112390812A
Application number: CN201910750632.2A
Authority: CN
Inventors: 李丕旭; 王鹏; 陈嗣平
Original assignee: Zhejiang Yizhong Chemical Co ltd; Suzhou Pengxu Pharmatech Co ltd
Current assignee: Zhejiang Yizhong Chemical Co ltd; Suzhou Pengxu Pharmatech Co ltd
Priority date: 2019-08-14
Filing date: 2019-08-14
Publication date: 2021-02-23
Also published as: WO2021027937A1

Abstract

The invention discloses a crystal form, an amorphous form and a preparation method of a gonadotropin releasing hormone (GnRH) receptor antagonist drug Ruogeli, and relates to the field of chemical medicine. The crystal form provided by the invention has better stability in an amorphous form, and has great significance in the purification process of active ingredients of medicaments and the preparation process of the medicaments.

Description

Crystalline and amorphous solids of Ruogeli compounds and methods of making the same

Technical Field

The invention relates to the field of chemical medicine, and relates to a crystal form and an amorphous form of a medicine Ruugeli with gonadotropin releasing hormone (GnRH) antagonistic activity and a preparation method thereof.

Background

Ruogeli (Relugolix) is a small molecule gonadotropin releasing hormone (GnRH) receptor antagonist developed and developed by Nippon Wuta drug Co., Ltd, and is capable of rapidly lowering female estrogen and progestin. Relogeli was approved for marketing in japan at 1 month 2019 and was approved for the treatment and symptom relief of uterine fibroids. New drug applications are expected to be submitted by the FDA in the third quarter of 2019.

The Ruugeli compound has a structure shown in a formula (I), and the chemical name of the Ruugeli compound is 1- (4- (1- (2, 6-difluorophenyl) -5- ((dimethylamino) methyl) -3- (6-methoxypyridazin-3-yl) -2, 4-dioxy-1, 2,3, 4-tetrahydrothiophene [2,3-d ] pyrimidine-6-yl) phenyl) -3-methoxyurea.

Methods for the preparation and isolation of rilogeli are described in patents (WO2014051164, CN104703992), disclosing one rilogeli tetrahydrofuran solvate crystal (CN 104703992 example 7) and one rilogeli crystal (CN 104703992 example 8).

Other patents (e.g., CN 100360538C) and literature reports (e.g., Journal of Medicinal Chemistry, 2011, 54, 4998-.

The form of the solid compound includes a crystalline form and an amorphous form. The crystal form of the compound also comprises a plurality of crystal form types such as single crystal of compound molecules and eutectic formed by the compound molecules and various solvents. Polymorphism of a compound refers to a state of matter in which two or more different crystal forms exist in the compound. Polymorphism is widespread in organic compounds. Different crystal forms of the same compound have obvious differences in the aspects of solubility, melting point, density, stability and the like, so that the stability and the uniformity of the compound are influenced to different degrees. Designing and using the proper specific crystal form in the process can improve the performance of the compound, such as better operability and stability. The ability to purify a compound during purification is a significant benefit by using specific amorphous solids or crystalline forms of crystallization. Therefore, comprehensive and systematic polymorphism and amorphous screening are performed in the process of drug development, and the selection of the most suitable developed solid form is one of important research contents which cannot be ignored.

Disclosure of Invention

The present application relates to new crystalline forms of Ruugeli, amorphous forms and methods of making the same.

In particular embodiments, it relates to crystalline forms of rilogeli, form M, form O1, form T, and form 03 and amorphous solids characterized by characterization of X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), thermogravimetric analysis ("TGA") and gas evolution analysis ("EGA") related data.

The invention also provides a method for preparing the crystalline Rulugol by the crystallization method. The Ruugeli starting material used therein may be prepared by any suitable method, including synthetic methods known in the art.

The crystal form M provided by the invention is characterized in that an X-ray powder diffraction pattern of the crystal form M has characteristic peaks at 2theta values of 7.8 +/-0.2 degrees, 8.6 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.7 +/-0.2 degrees and 23.3 +/-0.2 degrees.

Furthermore, the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 6.6 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.5 +/-0.2 degrees and 22.7 +/-0.2 degrees.

Further said form M is characterized by an X-ray powder diffraction pattern substantially in accordance with figure 1.

On the other hand, the application provides a method for preparing the crystal form M of the Ruugeli through cooling or evaporative crystallization and pulping in a mixed solution of the Ruugeli and a solvent.

In a specific embodiment, the crystalline form M of rilogeli is prepared by cooling or evaporative crystallization and slurrying in a mixed solution of rilogeli and isopropanol, diethyl carbonate, a 2-methyltetrahydrofuran/chloroform mixed solvent, and an isopropyl acetate/tetrahydrofuran mixed solvent.

Form M has a stability of greater than three days in an open room temperature state and greater than seven days in a sealed room temperature storage state.

In a specific embodiment, crystalline form M Ruugeli can be prepared by the methods of examples 1-4.

In a particular embodiment, crystalline form M of rilogeli is characterized by having a DSC curve shown in figure 2 and a TGA curve shown in figure 3.

The DSC curve for form M shows an endothermic peak at 168 ℃ (onset at 159 ℃), with sample melting or decomposition occurring above 177 ℃ (onset at 174 ℃).

The TGA curve did not show any weight loss before the compound decomposed, indicating that form M is not a solvate or hydrate form.

The invention provides Rugoly crystal form O1, which is characterized in that an X-ray powder diffraction pattern of the Rugoly crystal form O1 has characteristic peaks at 2theta values of 8.6 +/-0.2 degrees, 10.1 +/-0.2 degrees, 10.6 +/-0.2 degrees, 19.8 +/-0.2 degrees and 25.7 +/-0.2 degrees.

Further, the X-ray powder diffraction pattern thereof has characteristic peaks at 2theta values of 11.7. + -. 0.2 degrees, 12.9. + -. 0.2 degrees, 17.9. + -. 0.2 degrees, 21.4. + -. 0.2 degrees and 21.8. + -. 0.2 degrees.

Further said crystalline form O1, characterized by an X-ray powder diffraction pattern substantially in accordance with fig. 4.

In another aspect, the present application provides a process for preparing crystalline rilogeli form O1 by slurry crystallization at room temperature using p-xylene as a solvent.

In a specific embodiment, crystalline riluzeli form O1 may be prepared by the method reported in example 5.

Form O1 has a stability of greater than three days in an open room temperature state and a stability of greater than seven days in a sealed room temperature storage state.

In a particular embodiment, crystalline form O1 of rilogeli is characterized by having a DSC curve as shown in figure 5 and a TGA curve as shown in figure 6.

The DSC curve of form O1 shows that above 179 ℃ (starting at 168 ℃), melting or decomposition of the sample occurs. TGA showed a weight loss of 0.8% from 25 ℃ to 55 ℃, while no release of p-xylene or other solvents was detected by EGA, presumably the weight loss due to adsorbed water in the environment. The compounds degrade above 170 ℃.

The invention provides Rugoly crystal form T, which is characterized in that an X-ray powder diffraction pattern of the Rugoly crystal form T has characteristic peaks at 2theta values of 8.9 +/-0.2 degrees, 12.7 +/-0.2 degrees, 20.0 +/-0.2 degrees, 24.2 +/-0.2 degrees and 25.2 +/-0.2 degrees.

Further, the X-ray powder diffraction pattern thereof has characteristic peaks at 2theta values of 8.5. + -. 0.2 degrees, 11.0. + -. 0.2 degrees, 18.1. + -. 0.2 degrees, 19.1. + -. 0.2 degrees and 25.8. + -. 0.2 degrees.

Further said form T is characterized by an X-ray powder diffraction pattern substantially in accordance with figure 7.

In another aspect, the present application provides a crystalline form T of rilogeli obtained by cooling or crystallization using methyl tert-butyl ether, diethyl carbonate, tert-butyl acetate as anti-solvent using a solution of rilogeli in N, N-dimethylformamide.

In one embodiment, crystalline form T of rilogeli can be prepared by crystallization by the methods reported in examples 6-10.

Form T has a stability of greater than one day in an open room temperature state and greater than seven days in a sealed room temperature storage state.

In a particular embodiment, crystalline form T of relugori is characterized by having a DSC curve as shown in figure 8 and a TGA curve as shown in figure 9.

The DSC curve for form T shows the presence of three endothermic peaks, one at 141 ℃ with a gentle endotherm, one at 155 ℃ with a sharp endotherm released by the solvent, and 190.3 ℃ with an endotherm due to melting.

TGA had a 5.1% weight loss between 125 ℃ and 150 ℃, and comparison with EGA confirmed the weight loss solvent to be N, N-dimethylformamide. The molar ratio of Rulugol to N, N-dimethylformamide in the crystal form T is 1: 0.5, indicating that form T is a hemisolvate.

The invention provides a Ruugeli crystal form 03 which is characterized in that an X-ray powder diffraction pattern of the Ruugeli crystal form 03 has characteristic peaks at 2theta values of 7.5 +/-0.2 degrees, 9.5 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.2 +/-0.2 degrees and 23.2 +/-0.2 degrees.

Further, the X-ray powder diffraction pattern thereof has characteristic peaks at 2theta values of 12.1 + -0.2 deg., 15.5 + -0.2 deg., 16.8 + -0.2 deg., 21.1 + -0.2 deg. and 24.9 + -0.2 deg..

Further said crystalline form 03 characterized by an X-ray powder diffraction pattern substantially in accordance with figure 10.

In another aspect, the present application provides a method for preparing crystalline rilogeli form 03 by evaporation using acetonitrile, ethanol, 2-methyltetrahydrofuran, nitromethane or mixed solvents ethanol/chloroform, ethylene glycol dimethyl ether/methanol as solvents.

In one embodiment, crystalline form 03 of relugori can be prepared by crystallization by the methods reported in examples 11-20.

Form 03 has a stability of greater than forty days in a hermetically stored state at room temperature and greater than one hour in a hermetically stored state at 120 ℃.

In a particular embodiment, crystalline form 03 of relugori is characterized by having a DSC curve as shown in figure 11 and a TGA curve as shown in figure 12.

The DSC curve for form 03 shows the presence of two endothermic peaks, respectively an endothermic peak at 84 ℃ (onset temperature 63 ℃) due to solvent loss and an endothermic peak at 205.3 ℃ (onset temperature 201 ℃) due to melting endotherm.

The TGA curve shows a weight loss of 1.4% between 40 ℃ and 95 ℃. The molar ratio of Rulugol to water in the crystal form 03 is 1: 0.5, indicating the formation of hemihydrate. The presence of water has not been confirmed by other instrumentation. The compounds degrade above 200 ℃.

The invention provides a Ruugeli amorphous compound which is characterized in that an X-ray powder diffraction pattern of the Ruugeli amorphous compound has characteristic peaks at 2theta values of 5-15 degrees and 15-30 degrees.

Further the amorphous form is characterized by an X-ray powder diffraction pattern substantially in accordance with figure 13.

In another aspect, the present application provides a method for preparing a rilogeli amorphous compound by evaporation or temperature reduction using rilogeli with 3-pentanone, anisole, N, N-dimethylacetamide, N, N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, nitromethane, water, chloroform, 2-butanol, n-propanol, 1, 4-dioxane, toluene, benzonitrile, trimethylbenzene, benzyl alcohol, nitromethane, acetone, methyl ethyl ketone, dimethyl sulfoxide, formic acid, 3-methyln-butanol, anisole, cyclopentanone, cyclohexane, acetonitrile, dichloromethane, methyl acetate, or a mixture thereof as a solvent.

In one embodiment, Ruugeli amorphous forms can be prepared by evaporation or reduced temperature by the methods reported in examples 21-36.

The Ruugeli amorphous form has a stability of greater than one day in an open room temperature state and a stability of greater than seven days in a sealed room temperature storage state.

In a specific embodiment, the rilogeli amorphous form is characterized by having a DSC curve as shown in figure 14 and a TGA curve as shown in figure 15.

In yet another aspect, the present invention provides crystalline rilogeli forms of form C, form H, form I, form O2, form Q, and form Z, characterized by the consistent XRPD patterns reported in fig. 16. The above form C, form H, form I, form O2, form Q and form Z have a stability of more than one day in an exposed powder state and a stability of more than seven days in a sealed room temperature storage state. However, as the related crystallization process is not well studied, the reproducibility of the crystal form is relatively poor.

In another aspect, the present invention provides crystalline rilugeli forms of form a, form B, form D, form E, form F, form G, form J, form K, form L, form N, form P, form R, form S, form U and form V, characterized by the concordance of the XRPD patterns reported in fig. 17 and fig. 18. The above crystalline forms are unstable and easily transformed into other more stable crystalline forms.

Drawings

FIG. 1: an XRPD pattern of crystalline form M of rilogeli.

FIG. 2: DSC profile of rilogeli form M.

FIG. 3: a TGA profile of crystalline form M of rilogeli.

FIG. 4: an XRPD pattern of crystalline rilogeli form O1.

FIG. 5: a DSC profile of crystalline form O1 of rilogeli.

FIG. 6: a TGA profile of crystalline form O1 of rilogeli.

FIG. 7: an XRPD pattern of crystalline form T of rilogeli.

FIG. 8: DSC profile of rilogeli form T.

FIG. 9: a TGA profile of crystalline form T of rilogeli.

FIG. 10: an XRPD pattern of crystalline form 03 of rilogeli.

FIG. 11: a DSC profile of crystalline form 03 of rilogeli.

FIG. 12: a TGA profile of crystalline form 03 of rilogeli.

FIG. 13: an amorphous XRPD pattern of relogeli.

FIG. 14: DSC profile of the amorphous form of relogeli.

FIG. 15: a TGA profile of rilogeli amorphous.

FIG. 16: XRPD patterns of crystalline forms C, H, I, O2, Q, and Z of rilogeli.

FIG. 17: XRPD patterns of crystalline forms a, B, D, E, F, G, N, P, R, S and U of rilogeli.

FIG. 18: XRPD patterns of rilogeli crystalline forms J, K, L and V.

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 scope of protection of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

In the examples below, the test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the relogelide (compound I) was prepared by the method of example 11.

The abbreviations used in the present invention are explained as follows:

XRPD: powder X-ray diffraction

DSC: differential scanning calorimetry

TGA: thermogravimetric analysis

The X-ray powder diffraction pattern of the invention is collected on a Rigaku Miniflex 600X-ray diffraction powder diffractometer.

XRPD scanning parameter Start Position [ ° 2Th ]: 3; end Position [ ° 2Th ] 40; scan Step size 0.01 °; scan Speed 10 °/min; cu-anode (λ = 1.54 a); the voltage is 15 mA; current: 40 kV.

Differential Scanning Calorimetry (DSC) profiles described herein were collected on a Mettler Toledo DSC 1.

The method parameters for Differential Scanning Calorimetry (DSC) are as follows:

scanning range: 25-250 ℃; scanning rate: 10 ℃ per min

Protective gas: nitrogen gas

Thermogravimetric analysis (TGA) profiles described herein were collected on a Mettler Toledo TGA/DSC 1.

The process parameters for thermogravimetric analysis (TGA) are as follows:

scanning range: 25-320 ℃; scanning rate: 10 ℃ per min

Protective gas: nitrogen gas

Example 1

Preparing Ruogeli crystal form M:

adding Ruogeli into diethyl carbonate, heating to about 100 ℃ for dissolution, wherein the concentration is about 10 mg/mL, magnetically stirring and cooling to about 25 ℃, filtering to remove a crystal form F, placing the filtrate in an open laboratory for 17 hours, separating out a solid, and testing XRPD to show that the crystal form M is formed.

Example 2

Preparing Ruogeli crystal form M:

the Ruogeli is beaten in isopropanol at room temperature for 15 days to obtain crystal form P:

a 10 mg/mL isopropanol suspension of rilogeli was formulated, stirred at 25 ℃ for 15 days, the filter cake was collected by filtration, test XRPD showed form P, the filtrate was left in the laboratory for 23 h to precipitate a solid, test XRPD showed form M.

Example 3

Preparing Ruogeli crystal form M:

preparing 10 mg/mL of Ruugeli dimethylamine suspension, stirring at 25 ℃ for 15 days, filtering to collect a filter cake, testing XRPD of the wet filter cake, placing the wet filter cake in a laboratory for 23 hours, separating out a solid, and testing XRPD to show that the crystal form M is formed.

Example 4

Preparation of Ruogeli Crystal form M

Gradient cooling of isopropanol solution of Ruogeli to 10 ℃ to obtain crystal form M: heating 10 mg/mL isopropanol suspension of Ruugeli to 50 ℃ or higher for dissolving, then cooling to 10 ℃ at a cooling speed of 0.5 ℃ per min under magnetic stirring, filtering, and displaying a filter cake as a crystal form M by XRPD.

Example 5

Preparation of Ruogeli crystalline form O1

Preparing 10 mg/mL Rulugol p-xylene suspension, stirring at 25 ℃ for 15 days, filtering, collecting a filter cake, measuring XRPD to obtain a crystal form N, converting crystal form N powder into a mixed crystal of a crystal form O1 and a crystal form O2 after being exposed in the air for one day, continuing to perform crystal transformation for 7 days at room temperature to obtain a single crystal form, and measuring the single crystal form to obtain a crystal form O1 by XRPD.

Example 6

Preparation of Ruogeli crystal form T

The crystal form T is obtained by a method of dropwise adding methyl tert-butyl ether to an N, N-dimethylformamide solution of rilogeli: 1 mL of methyl tert-butyl ether was added dropwise to 0.2 mL of Ruugeli in N, N-dimethylformamide, stirred at room temperature, precipitated, stirred for 10 min, filtered and product tested XRPD showed form T.

Example 7

Preparation of Ruogeli crystal form T

The crystal form T is obtained by a method of dropwise adding diethyl carbonate into an N, N-dimethylformamide solution of rilogeli: dropwise adding 1 mL of diethyl carbonate into 0.2 mL of Ruugeli N, N-dimethylformamide solution, stirring at room temperature for 15 min, adding 1 mL of diethyl carbonate, stirring for 7 min, allowing precipitation to occur, continuing stirring for 10 min, filtering, and testing the product to obtain crystal form T shown by XRPD.

Example 8

Preparation of Ruogeli crystal form T

The crystal form T is obtained by a method of dropwise adding butyl acetate into an N, N-dimethylformamide solution of rilogeli: adding 1 mL of butyl acetate dropwise into 0.2 mL of Ruugeli N, N-dimethylformamide solution, stirring at room temperature for 15 min, adding 1 mL of butyl acetate, stirring for 5 min, allowing precipitation to occur, continuing stirring for 10 min, filtering, and testing XRPD to show crystal form T.

Example 9

Preparation of Ruogeli crystal form T

Crystalline form T is obtained by a process in which a solution of rilogeli in N, N-dimethylformamide is added dropwise to methyl tert-butyl ether with stirring at room temperature: 0.2 mL of rilogeli in N, N-dimethylformamide was added dropwise to 1 mL of methyl tert-butyl ether and stirred at 10 ℃ for 18 h, a solid precipitated and filtered, and the product tested XRPD showed form T.

Example 10

Preparation of Ruogeli crystal form T

Stirring the saturated solution of Ruogeli N, N-dimethylformamide at room temperature to obtain a crystal form T:

rilogeli (1.0152 g) was added to N, N-dimethylformamide (2.5 mL) at 25 ℃, stirred overnight at room temperature, filtered to remove insoluble material, the filtrate was allowed to stand at room temperature, solid precipitated, filtered and product test XRPD showed form T.

Example 11

Preparation of Ruogeli crystal form 03

Adding acetonitrile (4 mL) into a reaction bottle, adding CDI (0.56 g), starting stirring, adding TEA (0.16 g), cooling to 5-15 ℃, adding methoxylamine hydrochloride (0.29 g) in portions at the temperature controlled within 30 ℃, stirring and dissolving at 20-30 ℃, continuing stirring for 30 min, adding 6- (4-aminophenyl) -1- (2, 6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) thieno [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione (1.0 g), stirring for 2H at 45-55 ℃, adding triethylamine (0.24 g) at 45-55 ℃, dropwise adding water (4 mL), adding 40-50 ℃, stirring for 1H, and (3) separating out solids, dropwise adding water (10 mL) at the temperature of 40-50 ℃, cooling to 20-30 ℃, stirring for 1h, performing suction filtration, leaching a filter cake with a mixed solution of acetonitrile and water (the acetonitrile/water content is 1/4, totally 2 mL), adding the filter cake into tetrahydrofuran (5 mL), stirring for 1h at the temperature of 55-65 ℃, cooling to 0-10 ℃, stirring for more than 2 h, filtering, leaching the filter cake with 1 mL of tetrahydrofuran, and displaying that the XRPD is crystal form 03 in a product test.

Example 12

Preparation of Ruogeli crystal form 03

The crystal form 03 is obtained by a method of volatilizing an acetonitrile solution of Ruogeli at a low temperature:

preparing 10 mg/mL Rulugol acetonitrile solution at 25 ℃, stirring for 60 min at 25 ℃, dissolving, filtering the solution by using an organic filter head (25 mm/0.45 mu m), volatilizing the obtained filtrate at 10 ℃, and displaying the product test XRPD as a crystal form 03.

Example 13

Preparation of Ruogeli crystal form 03

Obtaining the crystal form 03 by a method of volatilizing an acetonitrile solution of Ruogeli at room temperature:

preparing 10 mg/mL Rulugol acetonitrile solution at 25 ℃, stirring for 60 min at 25 ℃, dissolving, filtering the solution by using an organic filter head (25 mm/0.45 mu m), volatilizing the obtained filtrate at room temperature to obtain a solid, and displaying the solid as a crystal form 03 by a product test XRPD.

Example 14

Preparation of Ruogeli crystal form 03

The crystal form 03 is obtained by a method of volatilizing an ethanol solution of Ruogeli at room temperature:

preparing 10 mg/mL Rulugol ethanol solution at 25 ℃, stirring for 60 min at 25 ℃, dissolving, filtering the solution by using an organic filter head (25 mm/0.45 mu m), volatilizing the obtained filtrate at room temperature to obtain a solid, and displaying the solid as a crystal form 03 by a product test XRPD.

Example 15

Preparation of Ruogeli crystal form 03

The crystal form 03 is obtained by a method of volatilizing an ethanol solution of Ruogeli at a low temperature:

preparing 10 mg/mL Rulugol ethanol solution at 25 ℃, stirring for 60 min at 25 ℃, dissolving, filtering the solution by using an organic filter head (25 mm/0.45 mu m), volatilizing the obtained filtrate at 10 ℃ to obtain a solid product, and testing XRPD to show that the solid product is crystal form 03.

Example 16

Preparation of Ruogeli crystal form 03

Obtaining a crystal form 03 by a method of volatilizing a 2-methyltetrahydrofuran solution of Ruogeli at room temperature:

preparing a 10 mg/mL Rulugol 2-methyltetrahydrofuran solution at 25 ℃, stirring for 60 min at 25 ℃, dissolving, filtering the solution by using an organic filter head (25 mm/0.45 mu m), volatilizing the obtained filtrate at room temperature to obtain a solid product, and testing the XRPD to show that the crystal form 03 is obtained.

Example 17

Preparation of Ruogeli crystal form 03

Obtaining a crystal form 03 by a method of volatilizing a 2-methyltetrahydrofuran solution of Ruogeli at a low temperature:

preparing a 10 mg/mL Rulugol 2-methyl tetrahydrofuran solution at 25 ℃, stirring for 60 min at 25 ℃, dissolving, filtering the solution by using an organic filter head (25 mm/0.45 mu m), volatilizing the obtained filtrate at about 10 ℃ to obtain a solid product, and displaying the solid product as a crystal form 03 by testing XRPD.

Example 18

Preparation of Ruogeli crystal form 03

The crystal form 03 is obtained by a method of volatilizing a nitromethane solution of Ruogeli at a low temperature:

preparing a 10 mg/mL Rulugol nitromethane solution at 25 ℃, stirring for 60 min at 25 ℃, dissolving, filtering the solution by using an organic filter head (25 mm/0.45 mu m), volatilizing the obtained filtrate at about 10 ℃ to obtain a solid product, and testing the XRPD to show that the crystal form 03 is obtained.

Example 19

Preparation of Ruogeli crystal form 03

The crystal form 03 is obtained by a method of volatilizing an ethanol-chloroform solution of Ruogeli at a low temperature:

preparing 10 mg/mL Rulugol ethanol-chloroform (v/v =1: 1) solution at 25 ℃, stirring for 60 min at 25 ℃, dissolving, filtering the solution by using an organic filter head (25 mm/0.45 mu m), and standing the filtrate at 10 ℃ to obtain a solid product, wherein the test XRPD shows that the crystal form 03 is formed.

Example 20

Preparation of Ruogeli crystal form 03

The crystal form 03 is obtained by a method of volatilizing glycol dimethyl ether-methanol solution of Ruogeli at low temperature:

Example 21

Preparing Ruogeli amorphous:

preparing 10 mg/mL Rulugol 3-pentanone, acetone, methyl acetate, methyl ethyl ketone, tetrahydrofuran, ethyl formate/acetone, chloroform/methyl acetate, methyl acetate/methanol, acetonitrile/methyl ethyl ketone, dichloromethane/methyl acetate and methyl ethyl ketone/ethylene glycol dimethyl ether solutions respectively, stirring the solutions at 25 ℃ for 60 min to completely dissolve the solutions, filtering the solutions by using an organic filter head (25 mm/0.45 mu m), standing the obtained filtrate at 10 ℃, filtering to obtain a solid product, and testing XRPD to show that the solid product is amorphous.

Example 22

Preparing Ruogeli amorphous:

preparing 10 mg/mL Rulugol 3-pentanone, acetone, chloroform, dichloromethane, ethylene glycol dimethyl ether, formic acid, methyl acetate, methyl ethyl ketone, methanol, nitromethane, tetrahydrofuran, n-propanol/1, 4-dioxane, ethyl formate/acetone, dichloromethane/acetone, chloroform/methyl acetate, methyl acetate/methanol, acetonitrile/methyl ethyl ketone, acetonitrile/3-pentanone, dichloromethane/methyl acetate and methyl ethyl ketone/ethylene glycol dimethyl ether solutions respectively, the solution was stirred at 25 ℃ for 60 min to dissolve completely, the solution was filtered with an organic filter head (25 mm/0.45 μm), the filtrate was allowed to stand at 25 ℃ and filtered to give a solid product, which was shown to be amorphous by test XRPD.

Example 23

Preparing Ruogeli amorphous:

10 mg/mL Rulugol 3-pentanone, anisole, N-dimethylacetamide, N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, nitromethane, ethanol/chloroform, 2-butanol/N, N-dimethylformamide, N-propanol/1, 4-dioxane, toluene/benzonitrile, trimethylbenzene/benzyl alcohol, nitromethane/N, N-dimethylformamide, acetone/methyl ethyl ketone, dimethyl sulfoxide/benzonitrile, water/formic acid, 3-methyln-butanol/N, N-dimethylacetamide, anisole/cyclopentanone, cyclohexane/N, N-dimethylacetamide, N-dimethylformamide, N, Acetonitrile/3-pentanone, dichloromethane/methyl acetate and methyl ethyl ketone/ethylene glycol dimethyl ether solution, stirring the solution at 25 ℃ for 60 min to completely dissolve the solution, filtering the solution by using an organic filter head (25 mm/0.45 mu m), injecting the solution into an 8 mL glass vial (a needle is inserted on a bottle stopper), heating the solution to 60 ℃ to volatilize, and obtaining a solid product, wherein the test XRPD shows that the solid product is amorphous.

Example 24

Preparing Ruogeli amorphous:

respectively preparing 10 mg/mL Rulugol 3-pentanone, acetonitrile, ethanol, methyl ethyl ketone, methanol, 2-methyltetrahydrofuran, nitromethane, tetrahydrofuran, ethanol/chloroform, n-propanol/1, 4-dioxane, acetonitrile/methyl ethyl ketone, ethylene glycol dimethyl ether/methanol, water/formic acid, acetonitrile/3-pentanone and methyl ethyl ketone/ethylene glycol dimethyl ether solution, stirring the solution at 25 ℃ for 60 min to completely dissolve the solution, filtering the solution by using an organic filter head (25 mm/0.45 mu m), injecting the solution into an 8 mL glass vial (a needle is inserted on a bottle stopper), and carrying out reduced pressure crystallization at 25 ℃ to obtain a solid product, wherein the test XRPD shows that the solid product is amorphous.

Example 25

Preparing Ruogeli amorphous:

respectively preparing 10 mg/mL Rulugol 3-pentanone, acetonitrile, ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, nitromethane, ethanol/chloroform, n-propanol/1, 4-dioxane, acetonitrile/methyl ethyl ketone, acetonitrile/3-pentanone and methyl ethyl ketone/ethylene glycol dimethyl ether solutions, stirring the solutions at 25 ℃ for 60 min to completely dissolve the solutions, filtering the solutions by using an organic filter head (25 mm/0.45 mu m), injecting the solutions into 8 mL glass vials (a needle is inserted on a bottle stopper), and carrying out reduced pressure crystallization at 40 ℃ to obtain solid products, wherein the test XRPD shows that the solid products are amorphous.

Example 26

Preparing Ruogeli amorphous:

turbid liquids of acetonitrile, methyl acetate and methyl ethyl ketone of Ruugeli are prepared respectively, the solution is stirred for 60 min at 25 ℃, the turbid liquid is filtered by an organic filter head (25 mm/0.45 mu m), the obtained filtrate is kept still at 10 ℃, a solid product is obtained by filtering, and test XRPD shows that the solution is amorphous.

Example 27

Preparing Ruogeli amorphous:

preparing turbid liquids of acetonitrile and methyl acetate of Ruugeli respectively, stirring the solution at 25 ℃ for 60 min, filtering the turbid liquid by using an organic filter head (25 mm/0.45 mu m), standing the obtained filtrate at 25 ℃, filtering to obtain a solid product, and testing XRPD (X-ray diffraction pattern) to show that the solid product is amorphous.

Example 28

Preparing Ruogeli amorphous:

preparing turbid liquids of acetonitrile, ethanol and nitromethane of Ruogeli respectively, stirring the solution at 25 ℃ for 60 min, filtering the turbid liquids by using an organic filter head (25 mm/0.45 mu m), standing the obtained filtrate at 60 ℃, filtering to obtain a solid product, and testing XRPD (X-ray diffraction pattern) to show that the solid product is amorphous.

Example 29

Preparing Ruogeli amorphous:

preparing suspensions of acetonitrile, ethanol, methyl ethyl ketone and nitromethane of Ruogeli respectively, stirring the solution at 25 ℃ for 60 min, filtering the suspension by using an organic filter head (25 mm/0.45 mu m), injecting the obtained filtrate into a 8 mL glass vial (a needle is inserted on a bottle stopper), and performing reduced pressure evaporation and crystallization at 25 ℃ to obtain a solid product, wherein the test XRPD shows that the solid product is amorphous.

Example 30

Preparing Ruogeli amorphous:

preparing turbid liquids of acetonitrile, methyl acetate, methyl ethyl ketone and nitromethane of Ruogeli respectively, stirring the solution at 25 ℃ for 60 min, filtering the turbid liquid by using an organic filter head (25 mm/0.45 mu m), injecting the obtained filtrate into a 8 mL glass vial (a needle is inserted on a bottle stopper), and carrying out reduced pressure evaporation and crystallization at 40 ℃ to obtain a solid product, wherein the test XRPD shows that the solid product is amorphous.

Example 31

Preparing Ruogeli amorphous:

water (1 mL) was added dropwise to a saturated solution of relugeli in 2-methoxyethanol (0.2 mL) with stirring at room temperature, the solid precipitated immediately, stirring was continued at room temperature for 10 min, and filtration gave a wet product which was amorphous by test XRPD.

Example 32

Preparing Ruogeli amorphous:

a saturated solution of rilogeli in 2-methoxyethanol (0.2 mL) was added dropwise to water (1 mL) with stirring at room temperature, the solid immediately precipitated, stirring was continued at room temperature for 10 min, and filtration gave a wet product which was amorphous by test XRPD.

Example 33

Preparing Ruogeli amorphous:

water (1 mL) was added dropwise to a saturated solution of rilogeli in tetrahydrofuran (0.2 mL) with stirring at room temperature, whereupon a solid precipitated immediately, stirring was continued at room temperature for 10 min, and the wet product was filtered and tested by XRPD.

Example 34

Preparing Ruogeli amorphous:

saturated tetrahydrofuran solution of Ruogeli (0.2 mL) was added dropwise to water (1 mL) with stirring at room temperature to precipitate a solid immediately, stirring at room temperature was continued for 10 min, and filtered to give a wet product which was amorphous by XRPD testing.

Example 35

Preparing Ruogeli amorphous:

water (1 mL) was added dropwise to a saturated solution of rilogeli in N, N-dimethylformamide (0.2 mL) with stirring at room temperature, whereupon a solid immediately precipitated, stirring was continued at room temperature for 10 min, and filtration gave a wet product which was amorphous by XRPD test.

Example 36

Preparing Ruogeli amorphous:

saturated solution of Ruogeli in N, N-dimethylformamide (0.2 mL) was added dropwise to water (1 mL) with stirring at room temperature, the solid immediately precipitated, stirring was continued at room temperature for 10 min, and the filtrate was filtered to give a wet product which was amorphous by XRPD testing.

Claims

1. A crystal form M of a compound Ruugeli is characterized in that an X-ray powder diffraction pattern of the crystal form M has characteristic peaks at 2theta values of 7.8 +/-0.2 degrees, 8.6 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.7 +/-0.2 degrees and 23.3 +/-0.2 degrees.

2. Form M according to claim 1, having an X-ray powder diffraction pattern with characteristic peaks at 2theta values of 6.6 ± 0.2 °, 15.0 ± 0.2 °, 15.5 ± 0.2 °, 22.7 ± 0.2 °.

3. A crystal form O1 of a compound Ruogeli, characterized in that an X-ray powder diffraction pattern thereof has characteristic peaks at 2theta values of 8.6 +/-0.2 degrees, 10.1 +/-0.2 degrees, 10.6 +/-0.2 degrees, 19.8 +/-0.2 degrees and 25.7 +/-0.2 degrees.

4. Form O1 according to claim 3, having an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 11.7 ± 0.2 °, 12.9 ± 0.2 °, 17.9 ± 0.2 °, 21.4 ± 0.2 ° and 21.8 ± 0.2 °.

5. A crystal form T of a compound Ruugeli is characterized in that an X-ray powder diffraction pattern of the crystal form T has characteristic peaks at 2theta values of 8.9 +/-0.2 degrees, 12.7 +/-0.2 degrees, 20.0 +/-0.2 degrees, 24.2 +/-0.2 degrees and 25.2 +/-0.2 degrees.

6. Form T according to claim 5, having an X-ray powder diffraction pattern with characteristic peaks at 2theta values of 8.5 ± 0.2 °, 11.0 ± 0.2 °, 18.1 ± 0.2 °, 19.1 ± 0.2 ° and 25.8 ± 0.2 °.

7. A crystal form 03 of a compound Ruugeli, characterized in that an X-ray powder diffraction pattern thereof has characteristic peaks at 2theta values of 7.5 +/-0.2 degrees, 9.5 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.2 +/-0.2 degrees and 23.2 +/-0.2 degrees.

8. The crystalline form 03 of claim 7 having an X-ray powder diffraction pattern with characteristic peaks at 2theta values of 12.1 ± 0.2 °, 15.5 ± 0.2 °, 16.8 ± 0.2 °, 21.1 ± 0.2 ° and 24.9 ± 0.2 °.

9. An amorphous form of the compound rilogeli characterized by an X-ray powder diffraction pattern having two characteristic peaks at 2theta values of 5 ° to 15 °, 15 ° to 30 °.

10. A preparation method of a compound Ruugeli crystal form M is characterized in that Ruugeli and a mixed solution of a solvent are subjected to cooling or evaporative crystallization and pulping to prepare the Ruugeli crystal form M.

11. The production process according to claim 10, wherein the solvent is isopropyl alcohol, diethyl carbonate, a mixed solvent of 2-methyltetrahydrofuran/chloroform, or a mixed solvent of isopropyl acetate/tetrahydrofuran.

12. A preparation method of a compound Ruugeli crystal form O1 is characterized in that Ruugeli is stirred in a paraxylene system to obtain a crystal form O1.

13. A preparation method of a compound Ruugeli crystal form T is characterized in that Ruugeli crystal form T is prepared by cooling or evaporating and crystallizing or dripping an antisolvent into an N, N-dimethylformamide solution of Ruugeli.

14. The method according to claim 14, wherein the anti-solvent is methyl tert-butyl ether, diethyl carbonate, tert-butyl acetate.

15. A preparation method of a compound Ruugeli crystal form 03 is characterized by comprising the step of crystallizing Ruugeli in an organic solvent through an evaporation solvent to obtain the crystal form 03.

16. The preparation method according to claim 15, wherein the organic solvent is acetonitrile, ethanol, 2-methyltetrahydrofuran, nitromethane or a mixed solvent of ethanol/chloroform, ethylene glycol dimethyl ether/methanol.

17. A preparation method of a compound Ruugeli amorphous compound is characterized in that Ruugeli and a solvent are mixed to prepare a crystalline Ruugeli amorphous compound in an evaporation or cooling mode.

18. The method of claim 17, wherein the solvent is 3-pentanone, anisole, N, N-dimethylacetamide, N, N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, nitromethane, water, chloroform, 2-butanol, n-propanol, 1, 4-dioxane, toluene, benzonitrile, trimethylbenzene, benzyl alcohol, nitromethane, acetone, methyl ethyl ketone, dimethyl sulfoxide, formic acid, 3-methyln-butanol, anisole, cyclopentanone, cyclohexane, acetonitrile, dichloromethane, methyl acetate, or a mixture thereof.

19. A pharmaceutical or pharmaceutical composition of a compound according to claims 1-18, prepared in crystalline or amorphous form.