WO2015074281A1

WO2015074281A1 - Rigosertib salt, crystal form thereof, and their preparation method and application

Info

Publication number: WO2015074281A1
Application number: PCT/CN2013/087793
Authority: WO
Inventors: 胡晨阳; 盛晓霞; 盛晓红
Original assignee: 杭州普晒医药科技有限公司
Priority date: 2013-11-25
Filing date: 2013-11-25
Publication date: 2015-05-28
Also published as: CN104884128A; CN104884128B

Abstract

The present application relates to rigosertib salt and a crystal form thereof. Compared with existing rigosertib salt, the rigosertib salt and the crystal form thereof in the present application has advantages on crystallinity, crystal habit, hygroscopicity, and stability. In addition, the present application further relates to a preparation method for the rigosertib salt and the crystal form thereof, pharmaceutical compositions, and their applications in preparing drugs for treating solid tumor disease.

Description

Ligesite salt and its crystal form, their preparation method and use

This application relates to the field of medicinal chemical crystallization technology. Specifically, it relates to a salt of the antitumor drug ligastide and a crystal form thereof, and to a method for preparing the salt and a crystal form thereof, a pharmaceutical composition thereof and use thereof. Background technique

The chemical name of the small molecule antitumor compound developed by Onconova Therapeutics is (E)-2,4,6-trimethoxyoxystyryl-3-(carboxyamido)-4-pyrene Oxybenzyl sulfone, also known as (E)-2-(5-((2,4,6-trimethoxyoxystyrenesulfonyl)indolyl)-2-nonyloxyanilino)acetic acid. The English name is Rigosertib, the alias is ON01910. Its chemical structure is as follows:

Riggside is a multi-kinase inhibitor that targets the mitotic and PLK kinase pathways. The drug has cell death activity and can act on 94 different tumor cell lines; it also inhibits some multi-drug resistant tumor cell lines and promotes the activity of chemotherapeutic agents in drug-resistant tumors. Current clinical trials use forceazide sodium salt, indications include myelodysplastic syndrome (MDS), leukemia, lymphoma, ovarian cancer, pancreatic cancer, lung cancer, advanced liver cancer, head and neck cancer, cervical cancer, esophageal cancer. Currently, the drug has begun in the clinical phase III of high-risk group MDS. The administration of ligastatin sodium salt includes intravenous injection and oral administration.

Patent documents WO2006074149 and WO2006104668 disclose Ligthatin compounds and synthetic methods thereof, the latter also providing a method for synthesizing the sodium salt thereof; Patent Document WO2008088803 describes a method for purifying Ringer Sodium salt, and simultaneously discloses the force grid game Dipotassium salt; Patent Document WO2008027049 discloses the melting point of ligastide, and discloses a method for synthesizing the sodium salt thereof; however, none of the above documents mentions the specific physical form, thermal analysis and other characterization data of the Ringer's salt. . In addition, MV Ramana Reddy et al. (J. Med. Chem. 2011, 54, 6254-6276) on Ringerdine sodium salt A description of the melting point and photosensitivity is carried out.

In the study, the applicant found that: the Ringer Sodium salt prepared according to WO2006104668 has no crystalline state and is amorphous; from the isothermal adsorption curve, it is very easy to absorb moisture, and the weight change is 21.5% at 20%~80% relative humidity. According to the oxidation stability test, the salt is easily oxidized and placed in a desiccator containing urea hydrogen peroxide for 5 days, and the purity is reduced by 34.58%. From the light stability experiment, the illumination is unstable, and the illumination condition is After 5 days of 45001x ± 5001x illumination, the purity was reduced by 11.98%.

In view of the deficiencies of the prior art, there is still a need in the art to develop Ringer's salt and crystalline forms which are more stable in nature and more advantageous for the manufacture of the drug. Summary of the invention

This application provides new Ringer's salt and its crystalline form, including Ringer's diethylamine salt, Riggsedrine calcium salt, and the crystalline forms of these salts.

The Ringer's diethylamine salt and its crystal form, Ringer's 4 bow salt and its crystal form of the present application have one or more superior properties compared to the known Ringer Sodium salt. For example, favorable crystallinity, preferred crystal form, low hygroscopicity, good stability, good fluidity and good processability.

One of the contents of the present application is to provide a Ringeride diethylamine salt and its crystal form A, Form B, Form C and a process for the preparation thereof.

The Ringeride diethylamine salt is a compound formed by a combination of Riggside and diethylamine in a molar ratio of 1:1, and has the structural formula shown below:

The preparation method of the Ringeride diethylamine salt adopts any one of the following methods:

(1) Forming a solution of Ringer's free acid in a soluble solvent, adding a diethylamine liquid to form a slurry and stirring, and concentrating the slurry to dryness to obtain the Ringeride diethylamine salt.

Preferably, the soluble solvent is selected from the group consisting of an alcohol or a ketone, preferably a d-C ₃ alcohol or a C ₃ -C ₄ ketone, wherein the C-C ₃ alcohol may be decyl alcohol, ethanol, n-propanol or iso The propanol, C ₃ -C ₄ ketone may be acetone or butanone; in an embodiment of the invention, the soluble solvent is more preferably ethanol or acetone.

Preferably, the molar ratio of the ligastide free acid to diethylamine is 1:1 to 1:10, preferably 1 : 2~1 : 5.

Preferably, the preparation temperature is room temperature, and the stirring time of the slurry is 10 to 24 hours, preferably 10 to 16 hours.

Preferably, the concentration of the ligastide free acid in the soluble solvent is 10 to 50 mg/mL, and preferably the concentration of the ligastide free acid in the alcohol solvent is 10 to 25 mg/mL, preferably The concentration of the freezer acid in the ketone solvent is 16-50 mg/mL.

The "concentration to dryness" can be carried out by conventional operations in the art, such as evaporation, distillation, volatilization, lyophilization, etc., preferably under reduced pressure, at a pressure of less than 0.09 MPa.

(2) Place the Riggside free acid in an environment filled with diethylamine gas to obtain a ligastide diethylamine salt.

Preferably, the standing temperature is room temperature, and the standing time is 1 to 3 days, preferably 1 to 2 days.

The preparation method is carried out, for example, in a large container containing diethylamine, and a small container containing ligastide free acid is placed, the small container is open, and the large container is sealed.

The Ringeride diethylamine salts obtained according to the above two preparation methods are all oily.

Preferably, the Ringeride diethylamine salt described in the present application is a Ringeride diethylamine salt crystal form B (hereinafter referred to as "diethylamine salt crystal form B"), the diethylamine salt crystal The X-ray powder diffraction pattern of the type B represented by the diffraction angle 2Θ has the following characteristic peaks: 4.4 ± 0.2°, 10.2 ± 0.2°, 11.7 ± 0.2°, 13.0 ± 0.2°,

20.9 ± 0.2 ° and 23.4 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the diethylamine salt crystal form B represented by the diffraction angle 2Θ has the following characteristic peaks: 4.4 ± 0.2°, 10.2 ± 0.2°, 11.7 ± 0.2°, 12.7 ± 0.2°, 13.0 ± 0.2°, 13.9 ± 0.2°,

16.4 ± 0.2°, 16.8 ± 0·2°, 17·5±0·2°, 19.6 ± 0·2°, 20.9 ± 0.2° and 23.4 ± 0.2°.

Further, the X-ray powder diffraction pattern of the diethylamine salt crystal form represented by the diffraction angle 2Θ has the following characteristic peaks and their relative intensities:

2Θ Relative strength%

4.4 ± 0.2° 37.2

10.2 ± 0.2° 100.0

11.7 ± 0.2. 68.0

12.7 ± 0.2. 43.2

13.0 ± 0.2. 88.7

13.9 ± 0.2° 46.1

16.4 ± 0.2. 43.4

16.8 ± 0.2° 40.0

17·5±0·2° 38.9 18.2 ± 0.2 ° 30.7

18.5士0·2 ^ο 27.2

19.6士0·2 ^ο 50.9

19.9 ± 0.2° 24.3

20.9士0·2 ^ο 62.7

22.1 ± 0.2 ° 33.0

22.7 ± 0.2 ° 32.2

23.4 ± 0.2. 87.6

24.1 ± 0.2° 50.0

24.3 ± 0.2 ° 36.7

24.6 ± 0.2. 29.5

26.1 ± 0.2. 53.2 ο

Without limitation, a typical example of the crystalline form of the diethylamine salt has an X-ray powder diffraction (XRPD) pattern as shown in FIG.

The diethylamine salt crystal form Β's polarized light microscopy (PLM) pattern is shown as fine crystalline particles.

The thermogravimetric analysis (TGA) pattern of the diethylamine salt crystal form B is shown in Fig. 10.

The differential thermal analysis (DSC) pattern of the diethylamine salt crystal form B showed a broad endothermic peak at 20 to 90 ° C, followed by a broad endothermic peak between 90 and 140 ° C.

The isothermal adsorption curve of the diethylamine salt form B showed a weight change of about 3.4% in the range of 20% to 80% relative humidity.

The Ringer's diethylamine salt crystal form B of the present application has the following beneficial effects as compared with the amorphous forceer sodium salt:

1) It can be seen from the XRPD pattern that the diethylamine salt crystal form B has higher crystallinity and crystal form, and has better fluidity and processability;

2) It is known from the isothermal adsorption curve that the diethylamine salt crystal form B has a low hygroscopicity;

3) It can be seen from the stability experiment that the diethylamine salt crystal form B has good chemical stability and crystal form stability: In the oxidation stability experiment, it is placed in a desiccator containing urea hydrogen peroxide for 5 days, purity The reduction was only 8.95% (amorphous Ringer's salt was 34.58%) and the crystal form remained unchanged. In the light stability experiment, when the illumination condition was 45001x ± 5001x illumination for 5 days, the purity was reduced by only 3.19% (the amorphous force of the Saide salt was 11.98%) and the crystal form remained unchanged.

Both of the above 2) and 3) indicate that the diethylamine salt form B of the present invention is better able to resist uneven content caused by external factors such as environmental moisture, light, oxygen, etc. during pharmaceutical preparation and/or storage. As well as problems such as reduced purity, it is more conducive to accurate quantification and post-transportation and storage in the preparation of unit preparations. And reduce the risk of decreased efficacy caused by unstable active substance content and increased impurity content.

The preparation method of the Ringeride diethylamine salt crystal form B comprises the following steps: The Ringeride diethylamine salt obtained according to the preparation method of the aforementioned Ringeride diethylamine salt is at a relative humidity of 75 Placed in an environment of %~85% to obtain the crystal form B of Ringer's diethylamine salt.

Preferably, the standing temperature is room temperature, and the standing time is 2 to 3 days, preferably 2 days.

Preferably, the relative humidity is preferably 85%.

Preferably, the Ringeride diethylamine salt described in the present application is a crystal form A of Ringeride diethylamine salt (hereinafter referred to as "diethylamine salt crystal form A"), the diethylamine salt crystal The X-ray powder diffraction pattern represented by the diffraction angle 2Θ of the type A has the following characteristic peaks: 4·3±0·2°, 11·2±0·2°, 16·2±0·2°, 17·0± 0·2°, 20.3±0.2° and 22.5±0.2°.

Further, the X-ray powder diffraction pattern represented by the diffraction angle 2Θ of the diethylamine salt crystal form has the following characteristic peaks: 4·3±0·2°, 11·2±0·2°, 11·5 ±0·2°, 12·1±0·2°, 13·5±0·2°, 14·2±0·2°, 16·0±0·2°, 16·2±0·2° , 17·0±0·2°, 19·9±0·2°, 20·3±0·2° and 22·5±0·2°.

Further, the X-ray powder diffraction pattern of the diethylamine salt crystal form represented by the diffraction angle 2? has the following characteristic peaks and their relative intensities:

2Θ Relative strength%

4·3±0·2° 79.0

11.2±0.2° 84.7

11.5±0.2° 43.1

12· 1±0·2° 39.5

13·5±0·2° 25.2

14.2±0.2° 30.3

16.0 ± 0.2 ° 43.9

16.2±0.2° 60.8

17.0±0.2° 100.0

18.9 ± 0.2 ° 15.7

19.9±0.2° 31.8

20·3±0·2° 66.5

22·5±0·2° 86.5

22.8±0.2° 38.8

23.6 ± 0.2 ° 17.3

23.9 ± 0.2 ° 59.4

24.2±0.2° 27.1

25.3 ± 0.2 ° 47.0

26.1±0.2° 26.1 ο Without limitation, a typical example of the diethylamine salt crystal form A has an X-ray powder diffraction (XRPD) pattern as shown in FIG.

The polarized light microscopy (PLM) pattern of the diethylamine salt crystal form A is shown as irregular bulk crystals.

The thermogravimetric analysis (TGA) of the diethylamine salt form A shows a weight loss of about 1.1% before 90 °C. The differential thermal analysis (DSC) pattern of the diethylamine salt form A shows two broad endothermic peaks between 110 ° C and 170 ° C.

The isothermal adsorption curve of the diethylamine salt crystal form A showed a weight change of about 2.5% in the range of 20% to 80% relative humidity.

The crystal form A of Ringer's diethylamine salt of the present application has the following beneficial effects as compared with the amorphous forceer sodium salt:

1) It can be seen from the XRPD pattern that the diethylamine salt crystal form A has higher crystallinity and crystal form, and has better fluidity and processability;

2) It is known from the isothermal adsorption curve that the diethylamine salt crystal form A has a low hygroscopicity.

The above 2) shows that the diethylamine salt crystal form A of the present invention can better cope with problems such as uneven content and reduced purity caused by external factors such as environmental moisture during the preparation and/or storage of the pharmaceutical preparation, and the like. It facilitates accurate quantification and post-transportation and storage in the preparation of unit preparations, and reduces the risk of deteriorating efficacy caused by unstable active substance content and increased impurity content.

The preparation method of the Ringerdidiamine salt crystal form A comprises the following steps: The Riggsedil diethylamine salt obtained according to the preparation method of the aforementioned Ringeride diethylamine salt is at a relative humidity of 92 Placed in an environment of %~97%, obtain the crystal form A of Ringer's diethylamine salt.

Preferably, the standing temperature is room temperature, and the standing time is 1 to 4 days, preferably 1 to 2 days.

Preferably, the relative humidity is preferably 92%.

Preferably, the Ringeride diethylamine salt described in the present application is a crystalline form of Ringer's diethylamine salt C (hereinafter referred to as "diethylamine salt crystal form C"), the diethylamine salt crystal The X-ray powder diffraction pattern of the type C represented by the diffraction angle 2 具有 has the following characteristic peaks: 7.1 ± 0.2 °, 11.3 ± 0.2 °, 12.5 ± 0.2 °, 17.7 ± 0.2 °, 18.7 ± 0.2 °, and 20.0 ± 0.2 °.

Further, the X-ray powder diffraction pattern of the diethylamine salt crystal form C represented by the diffraction angle 2Θ has the following characteristic peaks: 7.1 ± 0.2°, 9.4 ± 0.2°, 11.3 ± 0.2°, 11.7 ± 0.2°, 12.5 ± 0.2°, 17.2 ± 0.2°, 17.7 ± 0.2°, 18.7 ± 0.2°, 20.0 ± 0.2°, 21.8 ± 0.2°, 23.1 ± 0.2° and 24.1 ± 0.2°.

Further, the X-ray powder diffraction pattern of the diethylamine salt crystal form C represented by the diffraction angle 2 具有 has the following characteristic peaks and their relative intensities: 2Θ Relative strength%

7· 1±0·2° 100.0

9.4 ± 0.2° 13.8

11.3士0·2 ^ο 20.5

11.7 士0·2 ^ο 12.0

12.5 ± 0.2° 30.7

14.4 士 0.2° 7.0

15.6 ± 0.2 ° 6.5

17·2±0·2° 15.4

17.7 士 0.2° 18.7

18.7 ± 0.2 ° 22.3

20.0 ± 0.2. 18.7

20.7 ± 0.2. 9.4

21.1 ± 0.2. 12.3

21·5±0·2° 12.5

21.8±0.2° 21.1

22.7 ± 0.2. 13.9

23.1 ± 0.2 ° 24.6

23.6 ± 0.2. 10.9

24.1 ± 0.2 ° 27.7

24.4 ± 0.2. 17.3.

Without limitation, a typical example of the diethylamine salt crystal form C has the structure shown in FIG.

X-ray powder diffraction (XRPD) pattern.

The polarized light microscopy (PLM) pattern of the diethylamine salt crystal form C is shown as an irregular fine crystal.

The thermogravimetric analysis (TGA) pattern of the diethylamine salt crystal form C showed a weight loss of about 0.8% before 75 °C.

The differential thermal analysis (DSC) pattern of the diethylamine salt crystal form C shows a broad endothermic peak at 90 to 130 °C. The isothermal adsorption curve of the diethylamine salt crystal form C showed a weight change of about 9.9% in the range of 20% to 80% relative humidity.

The Ringer's diethylamine salt crystal form C of the present application has the following beneficial effects as compared with the amorphous force gemide sodium salt:

1) It can be seen from the XRPD pattern that the diethylamine salt crystal form C has higher crystallinity and crystal form, and has better fluidity and processability;

2) From the isothermal adsorption curve, the diethylamine salt crystal form C has a relatively low hygroscopicity.

The above 2) shows that the diethylamine salt crystal form C of the present invention can better cope with problems such as uneven content and reduced purity caused by external factors such as environmental moisture during pharmaceutical preparation and/or storage. It is more conducive to accurate quantification and post-transportation and storage in the preparation of unit preparations, and reduces the risk of decreased efficacy caused by unstable active substance content and increased impurity content.

The preparation method of the Ringerdidiamine salt crystal form C comprises the following steps: adding an organic solvent to the Ringeride diethylamine salt obtained according to the preparation method of the aforementioned Ringeride diethylamine salt The crystallizing is stirred, wherein the organic solvent is selected from the group consisting of an ester, a ketone or a mixture thereof to obtain the crystal form c of the Ringeride diethylamine salt.

Preferably, the organic solvent is c ₄ ~ c ₅ ester or c ₃ ~ c ₄ ketone, wherein the c ₄ ~ c ₅ ester may be ethyl acetate, propyl acetate, isopropyl acetate or ethyl propionate. The C c ₄ ketone may be acetone or methyl ethyl ketone; the organic solvent is more preferably ethyl acetate or acetone.

Preferably, the crystallization temperature is room temperature, and the crystallization time is 0.5 to 16 hours, preferably 0.5 to 8 hours.

Preferably, the mass to volume ratio of the Ringeride diethylamine salt to the organic solvent is 20 mg to 80 mg: 1 mL, preferably 50 mg to 80 mg: 1 mL.

The second content of the present application is to provide Ringer's 4 bow salt and its crystal form A, crystal form B and their preparation.

The Ringer's 4 Bow Salt is a compound formed by Ringeride and calcium ions in a molar ratio of 2:1, and its structural formula is as follows

The preparation method of the Ringer's 4 bow salt comprises the following steps: forming a solution of ligastide free acid in a soluble solvent, adding calcium hydroxide to form a slurry and stirring, separating the solid, washing with water, drying, and obtaining Lige Sai 4 bow salt.

Preferably, the molar ratio of the freezer acid to the calcium hydroxide is from 1:0.5 to 1:2, preferably from 1:1 to 1:1.5.

Preferably, the soluble solvent is selected from the group consisting of a ketone or an alcohol, preferably a C ₃ -C ₄ ketone or a d-C ₃ alcohol, the c ₃ -c ₄ ketone may be acetone, butanone, and the C-C ₃ alcohol may be hydrazine. Alcohol, ethanol, n-propanol or isopropanol; the soluble solvent is more preferably acetone or ethanol.

Preferably, the temperature of the slurry is room temperature, and the stirring time of the slurry is 10 to 24 hours, preferably Choose 10 to 16 hours.

Preferably, the concentration of the Ringer's free acid in the soluble solvent is 10 to 50 mg/mL, and preferably the concentration of the Liguestatin free acid in the ketone solvent is 10 to 50 mg/mL, more preferably 10~ 20 mg/mL; Preferably, the concentration of the ligastide free acid in the alcohol solvent is 10-20 mg/mL.

Preferably, the Ringer's 4 bow salt described in the present application is a Ringer's 4 bow salt crystal form A (hereinafter referred to as "calcium salt crystal form A"), and the 4 bow salt crystal form A is at a diffraction angle. The X-ray powder diffraction pattern indicated by 2Θ has the following characteristic peaks: 4·5±0·2°, 8·6±0·2°, 10·3±0·2°, 13·5±0·2°, 20·2±0·2° and 20·4±0·2°.

Further, the X-ray powder diffraction pattern represented by the diffraction angle of 2 弓 has the following characteristic peaks: 4.5±0.2°, 8.6±0.2°, 9.0±0.2°, 10.3±0.2°, 13.2± 0.2°, 13.5±0.2°, 14.1±0.2°, 17·3±0·2°, 18·7±0·2°, 20·2±0·2°, 20·4±0·2° and 24 ·0±0·2°.

Further, the X-ray powder diffraction pattern represented by the diffraction angle 2 所述 of the 4 丐 salt crystal form has the following characteristic peaks and their relative intensities:

2Θ Relative strength%

4·5±0·2° 58.3

8.6±0.2° 33.9

9.0±0.2° 37.1

10·3±0·2° 42.3

13.2±0.2° 37.1

13·5±0·2° 67.2

14· 1±0·2° 38.7

14.6±0.2° 26.4

15.9±0.2° 24.4

17·3±0·2° 29.8

18.7±0.2° 37.6

20.2 ± 0.2 ° 78.2

20.4±0.2° 100.0

24.0±0.2° 52.4

24·5±0·2° 30.1

27.0±0.2° 15.5

29.0±0.2° 19.9

Without limitation, a typical example of the 4-butter salt crystal form has an X-ray powder diffraction (XRPD) pattern as shown in Fig. 18.

Calcium salt crystal form A polarized light microscopy (PLM) pattern shows very fine irregular crystals.

The thermogravimetric analysis (TGA) pattern of the calcium salt form A showed a weight loss of about 4.7% before 150 °C. The differential thermal analysis (DSC) pattern of calcium salt crystal form A shows a broad endothermic peak at 130-170 °C. The isothermal adsorption curve of the calcium salt crystal form A shows that the weight change in the range of 20% to 80% relative humidity is about 0.5%.

The Ringer's 4 Bow Salt Crystal Form A of the present application has the following beneficial effects compared with the amorphous Ringerdine sodium salt:

1) It can be seen from the XRPD pattern that the calcium salt crystal form A has higher crystallinity and crystal form, and has better fluidity and processability;

2) From the isothermal adsorption curve, the calcium salt form A has a low hygroscopicity.

The above 2) shows that the calcium salt crystal form A of the present invention can better cope with problems such as uneven content and purity reduction caused by external factors such as environmental moisture in the process of pharmaceutical preparation and/or storage, and is more advantageous for the unit. Accurate quantification and later transport and storage in the preparation of the formulation, and reduce the risk of a decrease in efficacy due to unstable active substance content and increased levels of impurities.

The preparation method of the Ringer's 4 bow salt crystal form A comprises the following steps: stirring the Riggsetti 4 bow salt obtained according to the aforementioned method for preparing the Ringer's 4 bow salt in water to obtain Lige Saide 4 bow salt crystal form A.

Preferably, the mass to volume ratio of the Ringer's calcium salt to water is 5 mg to 10 mg: 1 mL, preferably 5 mg to 8 mg: lrtLL.

Preferably, the stirring temperature is room temperature, and the stirring time is 24 to 72 hours, preferably 24 to 36 hours. Preferably, the Ringer's 4 bow salt of the present application is a Ringer's 4 bow salt crystal form B (hereinafter referred to as "calcium salt crystal form B"), and the 4 bow salt crystal form B is at a diffraction angle. The X-ray powder diffraction pattern represented by 2Θ has the following characteristic peaks: 10·2±0·2°, 13·3±0·2°, 18·2±0·2°, 18·8±0·2°, 19·8±0·2° and 20·6±0·2°.

Further, the X-ray powder diffraction pattern represented by the diffraction angle of 2 弓 has the following characteristic peaks: 8·4±0·2°, 10·2±0·2°, 11·5± 0·2°, 13·3±0·2°, 14·4±0·2°, 14·8±0·2°, 18·2±0·2°, 18·8±0·2°, 19·8±0·2°, 20·6±0·2°, 23·2±0·2° and 25·3±0·2°.

Further, the calcium salt crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 具有 having the following characteristic peaks and their relative intensities:

2Θ Relative strength%

8.4±0.2° 11.7

10.2±0.2° 28.9

11·5±0·2° 18.8

13·3±0·2° 40.1

13.9±0.2° 17.0

14·4±0·2° 18.9 14.8 ± 0.2 ° 23.5

18.2 ± 0.2 ° 25.0

18.8 ± 0.2° 55.7

19.4士0·2 ^ο 21.4

19.8 ± 0.2 ° 44.8

20.6 ± 0.2. 100.0

21.5 ± 0.2. 25.3

21.9 ± 0.2° 32.4

23.2 ± 0.2. 44.9

23.9 ± 0.2. 35.6

25.3 ± 0.2. 76.4

25.9 ± 0.2. 39.7

27.9 ± 0.2. 37.0 ο

Without limitation, a typical example of the 4-butter salt crystal form has an X-ray powder diffraction (XRPD) pattern as shown in FIG.

Calcium salt crystal form The polarized light microscopy (PLM) pattern of yttrium is shown as a very fine irregular crystal.

Calcium salt crystal form The thermogravimetric analysis (TGA) pattern of strontium showed a weight loss of approximately 1.0% before 150 °C.

The differential thermal analysis (DSC) pattern of the calcium salt crystal form B shows a broad endothermic peak (melting peak) at 170 to 220 °C.

The isothermal adsorption curve of the calcium salt form B shows a weight change of about 0.4% in the range of 20% to 80% relative humidity.

The Ringer's 4 Bow Salt Form B of the present application has the following beneficial effects as compared with the amorphous Ringerdine sodium salt:

1) It can be seen from the XRPD pattern that the calcium salt crystal form B has higher crystallinity and crystal form, and has better fluidity and processability;

2) It is known from the isothermal adsorption curve that the calcium salt crystal form B has a low hygroscopicity;

3) It can be seen from the stability experiment that the calcium salt crystal form B has good chemical stability and crystal form stability. In the oxidative stability test, after 5 days in a desiccator containing urea hydrogen peroxide, the purity was reduced by 10.83% (amorphous force of the Saeedhi sodium salt was 34.58%) and the crystal form remained unchanged. In the light stability experiment, under the illumination condition of 45001x ± 5001x illumination for 5 days, the purity was reduced by only 2.19% (the amorphous force of the Saeki salt was 11.98%) and the crystal form remained unchanged. Both of the above 2) and 3) indicate that the calcium salt form B of the present invention is better able to resist the unevenness and purity caused by external factors such as environmental moisture, light, oxygen, etc. during the preparation and/or storage of the pharmaceutical preparation and/or storage. Reducing such problems is more conducive to accurate quantification and post-transportation and storage in the preparation of unit preparations, and reduces the risk of deteriorating efficacy caused by unstable active substance content and increased impurity content.

The preparation method of the Ringer's 4 bow salt crystal form B comprises the following steps: taking the Agathridin 4 丐 salt crystal form A, dissolving with dimethyl sulfoxide, adding water to crystallize, obtaining Lige Sai 4 bow salt crystal form B.

Preferably, the volume ratio of the dimercaptosulfoxide to water is from 1:5 to 1:10, preferably from 1:5 to 1:8.

Preferably, the strength of the Ringer's calcium salt crystal form A in the dimercapto sulfoxide is 40 to 60 mg/mL, preferably 40 to 50 mg/mLo.

Preferably, the crystallization temperature is room temperature, and the crystallization time is 5 to 24 hours, preferably 5 to 16 hours. In the present application, "crystalline" means confirmed by the X-ray powder diffraction pattern representation. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity. The map will usually change with the instrument conditions. The relative intensity of the peaks may vary with experimental conditions, so the order of peak intensities should not be the sole or decisive factor; the experimental error of the peak angle should also be taken into account, usually allowing soil 0.2. The error of the experimental factors such as the height of the sample causes an overall shift in the peak angle, which usually allows a certain offset. Thus, it will be understood by those skilled in the art that any crystal form having the same or similar characteristic peaks as the present application X-ray powder diffraction pattern is within the scope of the present application. The "single crystal form" means a single crystal form detected by X-ray powder diffraction.

The crystalline form of Ringer's salt as described herein is pure, single, and substantially free of any other crystalline or amorphous state. In this application, "substantially free" when used to refer to a new crystalline form means that the other crystalline form or amorphous form contained in the new crystalline form is less than 20% by weight, more preferably less than 10% by weight, especially Refers to less than 5% by weight, especially less than 1% by weight.

The "room temperature" as used herein means 10 to 30 °C.

In the production method of the present application, stirring is usually carried out unless otherwise specified. The stirring may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.

The "separation" described in the present application can be carried out by a conventional method in the art, such as filtration, centrifugation or the like. The specific operation of the filtration is as follows: The sample to be separated is placed on a filter paper, and filtered under reduced pressure. The specific operation of centrifugation is as follows: The sample to be separated is placed in a centrifuge tube, and then rotated at a high speed until the solid is completely sunk to the bottom of the centrifuge tube, and the centrifugation rate is, for example, 6000 rpm.

The "drying" described in the present application can be carried out by conventional methods in the art, such as blast drying and decompression. Drying, etc. The drying temperature is 30 to 50 ° C, preferably 30 to 40 ° C; and the drying time is 5 to 24 hours, preferably 5 to 16 hours. The pressure under reduced pressure was 0.09 MPa. The drying equipment is equipped with a fume hood, a forced air oven or a vacuum oven.

"Overnight" as used in this application refers to the time that the operation steps span the night, during which time the experimental phenomenon is not actively observed. The overnight time is 8 to 22 hours, preferably 10 to 18 hours, more preferably 16 hours.

The starting material of the present application, Ringer's free acid, can be obtained by the preparation method of Example 1 of the patent document WO2006104668. The comparative substance Ringeride sodium salt of the present application can be obtained by referring to the production method of Example 5 of the patent document WO2006104668.

Further, the present application provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more pharmaceutically active ingredients selected from the group consisting of the Ringer's salt of the present application and its crystalline form or The Ringeride salt and its crystalline form prepared by the preparation method of the present application, and at least one pharmaceutically acceptable carrier. Wherein the Ringer's salt and its crystal form of the present application include Ringeride diethylamine salt and its crystal form A, crystal form B and crystal form C, Lige Sai 4 bow salt and its crystal form A, crystal form B. Furthermore, the pharmaceutical composition may also comprise other pharmaceutically acceptable salts, crystal forms or amorphous forms of ligastide. Optionally, the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients.

Pharmaceutically acceptable carriers in the pharmaceutical compositions include, but are not limited to, diluents such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, mannose Alcohol, sorbitol, sugar, etc.; binders such as acacia, guar, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, copolyvidone, etc.; a disintegrating agent, such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; a lubricant such as stearin Acid, magnesium stearate, stearic acid, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silica; complex forming agents, such as various grades of cyclodextrin and resin; release rate Control agents such as hydroxypropylcellulose, hydroxydecylcellulose, hydroxypropylmethylcellulose, ethylcellulose, decylcellulose, decyl methacrylate, waxes and the like. Other pharmaceutically acceptable carriers that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like. In the case of oral tablets, commonly used carriers include lactose and corn starch, and lubricants such as magnesium stearate may also be added; in the case of oral capsules, useful carriers/diluents include lactose, high and low molecular weight poly Ethylene glycol and dry corn starch; in the case of gelatin capsules, powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like; when administered orally as a suspension, The active ingredient is mixed with emulsifying and suspending agents; if desired, certain sweetening and/or flavoring and/or coloring agents may be added. Every carrier must be acceptable It is compatible with the other ingredients in the formula and is harmless to the patient.

The pharmaceutical composition may be in a solid or liquid form, such as a solid oral dosage form, including tablets, granules, powders, pills, powders, and capsules; liquid oral dosage forms including solutions, syrups, suspensions, dispersions And emulsions; injectable preparations, including solutions, dispersions and lyophilizates. The formulation may be adapted for rapid release, delayed release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation. Routes of administration include oral administration, feeding through the stomach, feeding through the duodenum, intravenous, intra-arterial, intramuscular, subcutaneous, intraosseous, intradermal, intravaginal, intrarectal, intraperitoneal, transdermal, intranasal , eye drops, ear drops, etc.

The pharmaceutical composition can be prepared using methods well known to those skilled in the art. When preparing a pharmaceutical composition, the Ringer's salt of the present invention or a crystalline form thereof is mixed with one or more pharmaceutically acceptable carriers, optionally, with one or more other pharmaceutically active ingredients. . The solid preparation can be produced by a process such as direct mixing, granulation, or the like.

Further, the present application provides the Ringer's salt of the present application and its crystal form or the Ringer's salt obtained by the preparation method of the present application and its crystal form in the preparation of a medicament for treating and/or preventing solid tumor diseases. Use, wherein the salt of Ringeride and its crystal form of the present application include ligastide diethylamine salt and its crystal form A, crystal form B and crystal form C, Lige Saidi 4 bow salt and Form A, Form B, preferably the solid tumor disease is a solid tumor disease susceptible to treatment with a nucleotide analog chemotherapeutic agent.

The solid tumor diseases include, but are not limited to, malignant blood diseases such as leukemia, myelodysplastic syndrome, lymphoma, pancreatic cancer, liver cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, gastric cancer, bladder cancer, prostate cancer, colorectal Cancer, kidney cancer, esophageal cancer, biliary tract cancer, basal cell carcinoma, head and neck cancer, melanoma or glioma.

The nucleotide analog chemotherapeutic agent, including cladribine, clofarabine, f udarabine, mercaptopurine, pentostatin, Shu guanine (thioguanine), capecitabine (capecitabine), cytosine arabinoside (cytarabine), decitabine (decitabine), fluorouracil density ^σ ¹ ¾ (fluorouracil), floxuridine (floxuridine), Rocha Sapacitabine and gemcitabine. These compounds are structurally similar, typically by disrupting cell division or inhibiting the growth of relatively fast dividing cells, at least by interfering with DNA replication, thereby inhibiting tumor cell proliferation.

The solid tumor disease susceptible to treatment with a nucleotide analog chemotherapeutic agent can be understood as a patient who initially receives a nucleotide analog chemotherapeutic agent for treating a solid tumor disease and then develops into a nucleoside analog chemotherapeutic agent. It is resistant or has developed resistance. Susceptible nucleotide analogue Solid tumor diseases affected by therapeutic treatment include, but are not limited to, hematological malignancies such as leukemia, myelodysplastic syndrome, lymphoma, pancreatic cancer, liver cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, stomach cancer, bladder cancer, prostate Cancer, colorectal cancer, kidney cancer, esophageal cancer, biliary tract cancer, basal cell carcinoma, head and neck cancer, melanoma or glioma.

Further, the application provides a method of treating and/or preventing a solid tumor disease, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more of the Ringer's salt of the present application and a crystalline form thereof or a pharmaceutical composition thereof, wherein the Ringer's salt of the present application and its crystalline form include Ringer's diethylamine salt and its crystalline form A, crystalline form B and crystalline form C, Ligge Di 4 bow salt and its crystal form A, crystal form B, preferably the solid tumor disease is a solid tumor disease susceptible to treatment with a nucleotide analog chemotherapeutic agent, the patient refers to a mammal including a human .

When the solid tumor disease is a solid tumor disease susceptible to treatment with a nucleotide analog chemotherapeutic agent, the method comprises administering to a patient who is initially treated with a nucleotide analog chemotherapeutic agent to develop drug resistance, The claimed Ringer's salt and its crystalline form or a pharmaceutical composition thereof, or the use of the Ringer's salt of the present application and its crystalline form or a pharmaceutical composition thereof in combination with the nucleotide analog chemotherapeutic agent Treatment or combination therapy.

Brief Description of the Drawings Fig. 1 is a nuclear magnetic resonance spectrum of the Ringer's diethylamine salt of the present invention.

Figure 2 is an X-ray powder diffraction pattern of the crystalline form A of Ringer's diethylamine salt of the present invention.

Figure 3 is a PLM diagram of the crystalline form A of Ringeride diethylamine salt of the present invention.

Figure 4 is a DSC chart of Form A of Ringer's diethylamine salt of the present invention.

Figure 5 is a TGA diagram of Form A of Ringer's diethylamine salt of the present invention.

Fig. 6 is a graph showing the isothermal adsorption curve of the crystal form A of the Ringer's diethylamine salt of the present invention.

Figure 7 is an X-ray powder diffraction pattern of the crystalline form B of the Ringer's diethylamine salt of the present invention.

Figure 8 is a PLM diagram of Form B of Ringer's diethylamine salt of the present invention.

Figure 9 is a DSC chart of the crystalline form B of the Ringer's diethylamine salt of the present invention.

Figure 10 is a TGA diagram of Form B of Ringer's diethylamine salt of the present invention.

Fig. 11 is a graph showing the isothermal adsorption curve of the crystal form B of the Ringer's diethylamine salt of the present invention.

Figure 12 is an X-ray powder diffraction pattern of the crystalline form C of Ringeride diethylamine salt of the present invention.

Figure 13 is a PLM diagram of Form A of Ringer's diethylamine salt of the present invention. Figure 14 is a DSC chart of the crystalline form C of the Ringer's diethylamine salt of the present invention.

Figure 15 is a TGA diagram of the crystal form C of the Ringer's diethylamine salt of the present invention.

Figure 16 is a graph showing the isothermal adsorption curve of the crystalline form C of the Ringer's diethylamine salt of the present invention.

Figure 17 is a nuclear magnetic resonance spectrum of the Ringer's 4 bow salt of the present invention.

Figure 18 is an X-ray powder diffraction pattern of the Ringer's 4 Bow Salt Form A of the present invention.

Figure 19 is a PLM diagram of the Ringer's 4 Bow Salt Crystal Form A of the present invention.

Figure 20 is a DSC chart of the Ringer's 4 Bow Salt Crystal Form A of the present invention.

Figure 21 is a TGA diagram of the Ringer's 4 Bow Salt Form A of the present invention.

Figure 22 is a graph showing the isothermal adsorption curve of Ringer's 4 Bow Salt Crystal Form A of the present invention.

Figure 23 is an X-ray powder diffraction pattern of Ringer's 4 Bow Salt Form B of the present invention.

Figure 24 is a PLM diagram of the Ringer's 4 Bow Salt Form B of the present invention.

Figure 25 is a DSC chart of the Ringer's 4 Bow Salt Crystal Form B of the present invention.

Figure 26 is a TGA map of Ringer's 4 Bow Salt Form B of the present invention.

Figure 27 is an isotherm adsorption diagram of the Ringer's 4 Bow Salt Form B of the present invention.

Figure 28 is an X-ray powder diffraction pattern of Comparative Example 1 amorphous Ringer Sodium salt.

Figure 29 is a graph showing the isothermal adsorption curve of the amorphous 1 Ringer Sodium salt of Comparative Example 1. DETAILED DESCRIPTION OF THE INVENTION The present invention will be further understood by the following examples, but is not intended to limit the scope of the invention.

Testing equipment and methods:

The X-ray powder diffraction (XRPD) instrument is a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm under operating conditions of 40 kV and 40 mA, a Θ-2Θ goniometer, a Mo monochromator Lynxeye detector. . The instrument was tested with diamonds before use. The acquisition software is Diffrac Plus XRPD Commander, and the analysis software is MDI Jade 5.0. The sample is tested at room temperature and the sample to be tested is placed on a non-reflecting plate. The detailed detection conditions are as follows, angle range: 3-40 ° 2θ, step size: 0.02 ° 2 Θ, speed: 0.2 sec / step. Samples were not ground prior to testing unless otherwise stated.

Polarized light microscopy (PLM) spectra were taken from a ΧΡ-500 Ε polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on the stage of the ΧΡ-500Ε polarized light microscope, select the appropriate magnification Multiply observe the morphology of the sample and take a picture. The differential thermal analysis data was taken from the TA Instruments Q200 MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually take 1 - 10 mg of the sample in an uncoated (unless otherwise specified) aluminum crucible, at a temperature rise rate of 10 ° C / min, under the protection of ⁴⁰ mL / min dry N ₂ , the sample from 20 The °C rises to 200 °C, while the TA software records the change in heat during the temperature rise of the sample. In the present application, the melting point is reported as the starting temperature.

The thermogravimetric analysis data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. The sample of 5-15 mg was usually placed in a platinum crucible, using a segmented high-resolution detection method at 10°. The temperature rise rate of C/min was increased from room temperature to 300 °C under the protection of 40 mL/min dry N ₂ , while the TA software recorded the change in weight of the sample during the temperature increase.

Dynamic moisture adsorption analysis data and isothermal adsorption analysis data were taken from the TA Instruments Q5000 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. A sample of l-10 mg is usually placed in a platinum crucible, and the TA software records the change in weight of the sample during a change in relative humidity from 0% to 80% to 0%. Depending on the sample, different adsorption and desorption steps are also applied to the sample.

Nuclear magnetic resonance spectroscopy data (^HNMR) were taken from a Bruker Avance II DMX 400 MHZ NMR spectrometer. A sample of l-5 mg was weighed and dissolved in 0.5 mL of deuterated chloroform (CDC1 ₃ ) to prepare a solution of 2 mg/mL - 1 Omg/mL.

High performance liquid chromatography (HPLC) analysis data was taken from Agilent 1260 and ChemStation was B.04. The corresponding parameters are as follows: column 5micron C18 4.6x250mm, column temperature 35 °C, flow rate 1.Oml/min, mobile phase 80% acetonitrile and 20% water, wavelength 254nm, injection volume 20μ1 and run time 15 minutes.

The various reagents used in the examples were commercially available unless otherwise specified.

Preparation example 1

Preparation of ligastide free acid

The Riggside free acid was synthesized by the preparation method of Example 1 of the patent document WO2006104668. The specific operations are as follows:

Α)Synthesis (Ε)-2-(5-((2,4,6-三曱 ^^ phenylephedoyl) fluorenyl)-2-indoleanilide)

5 mmol of decyl bromoacetate and 5 mmol of sodium acetate were dissolved in 20 mL of decyl alcohol, and 1 mmol of (E)-5-((2,4,6-trimethoxy styrenesulfonyl) fluorenyl)-2- The mixture is heated under reflux with stirring for 12 to 15 hours. After cooling to room temperature, it is poured into ice water to precipitate a precipitate, which is filtered and dried in vacuo to give 0.74 mmol (E)-2-(5-((2,4) , 6-trimethoxy styrenesulfonyl) fluorenyl)-2-nonyloxyanilino) The acid ester was 74.0%.

B) Synthesis of (E)-2-(5-((2,4,6-trimethoxyoxystyrenesulfonyl)indolyl)-2-nonyloxyanilino)acetic acid

Add 4.0 mL of ethanol to 25.0 mL of an aqueous solution containing 4% sodium hydroxide, stir and mix well, then add 500 mg of (E)-2-(5-((2,4,6-trimethoxyoxystyrenesulfonyl)曱 ) ) ) ) ) ) 固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体, dried under vacuum, recrystallized from isopropanol to give 400 mg of (E)-2-(5-((2,4,6-trimethanesulfonyl)sulfonyl)-2-anthracepin Acetic acid (ie, Ringer's free acid), yield 82.5%. The melting point and nuclear magnetic resonance spectrum information of the product was determined to be consistent with that provided in the patent literature.

Comparative example 1

Preparation of Ringer Sodium Salt

The Rigastron sodium salt is prepared by the preparation method of Example 5 of the patent document WO2006104668. The specific operations are as follows:

800.0mg of Ligdisdi free acid is dissolved in 8.0 ml of ethanol, added with NaOH (70.0mg / 1.9ml water), adjusted to pH 7.5~8.0, stirred at room temperature for 1 hour, lowered to 0 ° C, filtered, washed with ethanol, then It was rinsed with n-hexane and dried in vacuo to give 700.5 mg of y.

The X-ray powder diffraction pattern of the amorphous Ringer Sodium salt is shown in Fig. 28.

The isotherm adsorption curve is shown in Figure 29, which shows that it is highly hygroscopic, with a weight change of 21.5% at 20% to 80% relative humidity.

Example 1

At room temperature, take 500.0mg of ligastide free acid, add 20mL of ethanol to dissolve, 160.0mg of diethylamine liquid slowly added to the solution of ligastide free acid in ethanol to form a slurry for 16 hours, 30 ° C vacuum concentration To the dryness, 512.3 mg of oily Ringeride diethylamine salt was obtained in a yield of 88.2%.

The nuclear magnetic resonance spectrum of Fig. 1 was confirmed to be Ringer's diethylamine salt, and the Ringer's free base and diethylamine were salted in a 1:1 molar ratio.

Nuclear magnetic resonance data _3⁄4 NMR (CDC1 ₃ , 500 MHz): 1.35 - 1.40 (m, 6H), 2.90-3.00 (m, 4H), 3.78-3.84 (m, 2H), 3.83 (s, 3H), 3.85 ( 3, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.18 (s, 2H), 6.10-6.15 (m, 2H), 6.54 (d, 1H, J = 0.2 Hz), 6.70-6.75 (m, 2H), 7.09 (d, , J = 15.5 Hz), 7.86 (d, 1H, J = 15.5 Hz).

HPLC determination: The actual content of ligastide free acid in the prepared ligastide diethylamine salt was 86.2%, which was equivalent to the theoretical content of 86.1%, indicating that the Liguedide free acid and diethylamine were 1: 1 Erbi into salt.

Example 2

At room temperature, take 25.0mg of ligastide free acid, add 2.5mL of sterol to dissolve, 20.0mg of diethylamine liquid slowly added to the solution of ligastide free acid in sterol solution to form a slurry for 24 hours, 30 ° C was concentrated to dryness in vacuo to give 23.2 mg of oily sigmadiamine salt, yield 79.9%. Example 3

At room temperature, take 250.0mg of ligastide free acid, add lO.OmL ethanol to dissolve, 40.0mg of diethylamine liquid slowly added to the solution of ligastide free acid in ethanol to form a slurry and stir for 16 hours, 30 ° C Concentration in vacuo to dryness afforded 230.2 mg of " Example 4

At room temperature, take 25.0mg of Riggside free acid, add 2.5mL of isopropanol to dissolve, and slowly add 4.0mg of diethylamine liquid to the solution of Riggside free acid in isopropanol to form a slurry, stir for 16 hours. It was concentrated to dryness under vacuum at 30 ° C to give 21.0 mg of the oily sigmadiethylamine salt in a yield of 72.3%. Example 5

At room temperature, 800.0 mg of ligastide free acid was added, dissolved in 50 mL of acetone, and 260.2 mg of diethylamine liquid was slowly added dropwise to the acetone solution of ligastide free acid to form a slurry, stirred for 10 hours, and concentrated at 30 ° C in vacuo. To the dryness, 850.2 mg of oily Ringeride diethylamine salt was obtained in a yield of 91.5%. Example 6

At room temperature, take 100.Omg of Riggside free acid, add 5mL of acetone to dissolve, 81.0mg of diethylamine liquid slowly added to the solution of Liguedide free acid in acetone to form a slurry for 16 hours, 30 ° C vacuum Concentrated to dryness to give 95.5 mg of the oily product of " Example 7

At room temperature, take 100.Omg of Ringer's free acid, add 2.0mL of acetone to dissolve, 16.2mg of diethylamine liquid slowly added to the acetone solution of Liguedide free acid to form a slurry and stir for 16 hours, 30 °C Concentration in vacuo to dryness gave 80.1 mg of EtOAc (EtOAc). Example 8

At room temperature, take 100.Omg of Riggside free acid, add 5mL of methyl ethyl ketone to dissolve, 162mg of diethylamine liquid slowly added to the solution of ligastide free acid in butanone to form a slurry, stir for 16 hours, 30 ° C was concentrated to dryness in vacuo to give 92.0 g of the oily sigmadiamine salt, yield 79.2%. Example 9

At room temperature, take lOO.Omg of Ringer's free acid and place it in a sealed volume filled with diethylamine gas. In the apparatus, oily Ringeride diethylamine salt was obtained after one day.

Example 10

At room temperature, lOO.Omg of Ringer's free acid was placed in a sealed container filled with diethylamine gas, and after 2 days, oily Ringeride diethylamine salt was obtained.

Example 11

At room temperature, lOO.Omg of Ringer's free acid was placed in a sealed container filled with diethylamine gas, and after 3 days, an oily Ringeride diethylamine salt was obtained.

The samples prepared in Examples 2 to 11 had the same or similar nuclear magnetic hydrogen spectroscopy and HPLC detection results (not shown) as the samples of Example 1, indicating that the samples of Examples 2 to 11 were the same as those of Example 1.

Example 12

At room temperature, take 100.Omg of the oily Ringeride diethylamine salt prepared by the invention, placed in a humidity chamber of 92% relative humidity for 2 days, and dried at 40 ° C to obtain 92.3 mg of white-like force. The ethylamine salt crystal form A, the yield was 92.3%.

The X-ray powder diffraction pattern of the diethylamine salt crystal form A is shown in Fig. 2.

The PLM spectrum of the diethylamine salt crystal form A is shown in Fig. 3 and is shown as an irregular bulk crystal.

The DSC spectrum of the diethylamine salt crystal form A is shown in Fig. 4.

The TGA spectrum of the diethylamine salt crystal form A is shown in Fig. 5.

The isothermal adsorption curve of the diethylamine salt crystal form A is shown in Fig. 6, showing a weight change of about 2.5% in the range of 20% to 80% relative humidity.

The above test results show that the crystal form A of Ringer's diethylamine salt has a good crystal state and morphology and has low hygroscopicity compared with the known Lige Sidi salt.

Example 13

40.0 mg of oily Ringeride diethylamine salt prepared by the present invention was placed in a humidity chamber of 92% relative humidity for 1 day at room temperature, and dried at 40 ° C to obtain 35.2 mg of white-like Liegedi di Amine salt crystal form A, yield 88.0%.

Example 14

At room temperature, 50.0 mg of the oily Ringeride diethylamine salt prepared by the present invention was placed in a humidity chamber of 97% relative humidity for 4 days and dried at 40 ° C to obtain 41.7 mg of white-like Ligedi di Amine salt crystal form A, yield 83.4%.

The samples prepared in Examples 13 to 14 have the same or similar X-rays as the sample of Example 12. A powder diffraction pattern, a DSC pattern, and a TGA pattern (not shown) indicate that the samples of Examples 13 to 14 were the same as the samples of Example 12.

Example 15

500.0 mg of oily Ringeride diethylamine salt prepared by the present invention was placed in a humidity chamber of 85% relative humidity for 2 days at room temperature, and dried at 40 ° C to obtain 455.6 mg of white-like force. Amine salt crystal form B, yield 91.1%.

The X-ray powder diffraction pattern of the diethylamine salt crystal form B is shown in Fig. 7.

The PLM spectrum of the diethylamine salt crystal form B is shown in Figure 8, which is shown as fine crystalline particles.

The DSC spectrum of the diethylamine salt crystal form B is shown in Fig. 9.

The TGA spectrum of the diethylamine salt crystal form B is shown in Fig. 10.

The isothermal adsorption curve of the diethylamine salt form B is shown in Fig. 11, showing a weight change of about 3.4% in the range of 20% to 80% relative humidity.

The above test results show that: Ringer's diethylamine salt crystal form B has a good crystalline state and morphology, and has low hygroscopicity compared with the known Lith spinach salt.

Example 16

50.0 mg of the oily Ringeride diethylamine salt prepared by the invention was placed in a humidity chamber of 75% relative humidity for 3 days at room temperature, and dried at 40 ° C to obtain 43.3 mg of white-like Liegedi di Amine salt crystal form B, yield 86.6%.

The sample prepared in Example 16 had the same or similar X-ray powder diffraction pattern, DSC pattern and TGA pattern (not shown) as the Example 15 sample, indicating that the sample of Example 16 was the same as the sample of Example 15.

Example 17

At room temperature, 300.0 mg of the oily Ringeride diethylamine salt prepared in the present invention was added, and 6.0 mL of ethyl acetate was added and stirred for 0.5 hour to obtain an off-white solid, which was filtered and dried under vacuum at 40 ° C overnight to obtain 288.1 mg of white. Ringer's diethylamine salt crystal form C, yield 96.0%,

The X-ray powder diffraction pattern of the diethylamine salt crystal form C is shown in Fig. 12.

The PLM spectrum of the diethylamine salt crystal form C is shown in Fig. 13, and it is shown as an irregular fine crystal.

The DSC spectrum of the diethylamine salt crystal form C is shown in Fig. 14.

The TGA spectrum of the diethylamine salt crystal form C is shown in Fig. 15.

The isothermal adsorption curve of the diethylamine salt crystal form C is shown in Fig. 16, showing a weight change of about 9.9% in the range of 20% to 80% relative humidity. The above test results show that: The Ringer's diethylamine salt crystal form C has a good crystal state and morphology, and has low hygroscopicity compared with the known Ringerdine salt.

Example 18

120 mg of the oily Ringeride diethylamine salt prepared in the present invention was stirred at room temperature for 8 hours by adding 1.5 mL of acetone to obtain an off-white solid, which was filtered and dried under vacuum at 40 ° C overnight to obtain 92.1 mg of white-like Ligedi. The diethylamine salt crystal form C, the yield was 76.8%.

Example 19

At room temperature, 120 mg of oily Ringeride diethylamine salt prepared by the invention was added, and 5.0 mL of butanone was added and stirred for 16 hours to obtain an off-white solid, which was filtered and dried under vacuum at 40 ° C overnight to obtain 88.0 mg of white-like force. Diethylamine salt crystal form C, yield 73.3%.

Example 20

120 mg of the oily Ringeride diethylamine salt prepared by the invention was added at room temperature, and 6.0 mL of isopropyl acetate was added and stirred for 10 hours to obtain an off-white solid, which was filtered and dried under vacuum at 40 ° C overnight to obtain 85.3 mg of white color. Gossip diethylamine salt crystal form C, yield 71.1%.

The samples prepared in Examples 18 to 20 had the same or similar X-ray powder diffraction patterns, DSC patterns and TGA patterns (not shown) as the samples of Examples 17, indicating that the samples of Examples 18 to 20 were identical to the samples of Example 17. Substance.

Example 21

At room temperature, take 800.0mg of ligastide free acid, add 40mL of acetone to dissolve, add 144.2mg of calcium hydroxide to the solution of ligastide free acid in acetone, stir a large amount of white solids for half an hour, stir for 16 hours, filter It was washed with water and dried under vacuum at 40 ° C overnight to obtain 770.2 mg of celathlon 4 ylide, yield 92.4%.

Figure 17 Nuclear magnetic hydrogen spectroscopy confirms that Lige Sidi has become a calcium salt.

Nuclear magnetic resonance data: 3⁄4 NMR (ί 6-DMSO, 500 MHz): 3.78 (s, 3H), 3.84 (s, 3H), 3.85 (3, 6H), 4.26 (s, 2H), 6.28 (s, 2H ), 6.37 (d, 1H, J = 1.5 Hz), 6.48-6.51 (m, 1H), 6.75 (d, 1H, J = 8.0 Hz), 7.10 (d, 1H, J = 16 Hz), 7.57 (d , lH, /= 16 Hz).

HPLC determination: The actual content of the Liguedide free acid in the prepared Ringer's 4 bow salt is 96.4%, which is equivalent to the theoretical content of 95.8%, indicating that Ringeride free acid and calcium hydroxide are 2:1. The molar ratio is salt.

Example 22

At room temperature, take lOO.Omg of Riggside free acid, add lO.OmL acetone to dissolve, take 25.0mg Calcium hydroxide was added to a solution of ligastide free acid in acetone, and a large amount of white solid was precipitated by stirring for 10 minutes, stirred for 10 hours, filtered, washed with water, and dried under vacuum at 40 ° C overnight to obtain 92.1 mg of celecide. The yield was 88.4%.

Example 23

At room temperature, take lOO.Omg of Ringer's free acid, add 5.0mL of methyl ethyl ketone dissolved, take 33.0mg of calcium hydroxide added to the solution of ligastide free acid in methyl ethyl ketone, stir for 5 minutes, a large amount of white solid precipitation, stirring After 24 hours, filtered, washed with water and dried under vacuum at 40 ° C overnight to give 85.9 mg of sig.

Example 24

At room temperature, take 100.Omg of Ringer's free hydrazine and add 2.0mL of acetone to dissolve. Take 8.2mg of calcium hydroxide and add it to the acetone solution of ligastide free acid. Stir a large amount of white solid for 20 minutes and stir for 24 hours. Filtration, washing with water, and drying under vacuum at 40 ° C overnight, afforded 72.2 mg of sig.

Example 25

At room temperature, take 100.Omg of Riggside free acid and add 10OmL of isopropanol to dissolve and take 25.0mg of calcium hydroxide to the solution of ligastide free acid in isopropanol and stir for about 10 minutes to precipitate a large amount of white solid. The mixture was stirred for 16 hours, filtered, washed with water, and dried under vacuum at 40 ° C overnight to give 76.6 mg of sigridin calcium salt, yield 73.5%.

Example 26

At room temperature, take 100.Omg of Ringer's free acid, add 5.0mL of decyl alcohol to dissolve, add 25.0mg of calcium hydroxide to the solution of ligastide free acid in methanol, stir a large amount of white solids for about 25 minutes, After stirring for 10 hours, filtration, washing with water, and drying under vacuum at 40 ° C overnight, 69.8 mg of celathlon 4 y salt was obtained in a yield of 67.0%.

Example 27

At room temperature, take 100.Omg of Ringer's free acid, add 5.0mL of ethanol to dissolve, add 25.0mg of calcium hydroxide to the solution of Liguedide free acid in ethanol, stir for about 15 minutes, a large amount of white solid precipitation, stirring 10 The mixture was filtered, washed with water, and dried under vacuum overnight at 40 ° C to give 88.5 mg of celathlon 4 y salt, yield 84.9%.

The samples prepared in Examples 22 to 27 had the same or similar nuclear magnetic hydrogen spectra and HPLC results (not shown) as the samples of Example 21, indicating that the samples of Examples 22 to 27 were the same as the samples of Example 21. Example 28

At room temperature, 300.0 mg of the Ringeride 4 丐 salt prepared by the present invention was placed in 60 mL of water, stirred for 36 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 242.5 mg of white Ringer's 4 bow salt crystal form A, The yield was 80.8%.

The X-ray powder diffraction pattern of the calcium salt crystal form A is shown in Fig. 18.

The PLM spectrum of the calcium salt crystal form A is shown in Figure 19 and is shown as a very fine irregular crystal.

The DSC spectrum of the calcium salt crystal form A is shown in Fig. 20.

The TGA spectrum of the calcium salt crystal form A is shown in Fig. 21.

The isothermal adsorption curve of the calcium salt crystal form A is shown in Fig. 22, showing a weight change of about 0.5% in the range of 20% to 80% relative humidity.

The above test results show that: Ringer's 4 bow salt crystal form A has good crystal morphology and morphology, and has low hygroscopicity.

Example 29

At room temperature, 120.0 mg of Ringer's 4 bow salt prepared in the present invention was placed in 15 mL of water, stirred for 24 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 93.6 mg of white Ringer's 4 bow salt crystal form A. The yield was 78.0%.

Example 30

At room temperature, 120.0 mg of Ringer's 4 bow salt prepared according to the present invention was placed in 12 mL of water, stirred for 72 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 88.7 mg of white Ringer's 4 bow salt crystal form A, The yield was 73.9%.

The samples prepared in Examples 29 to 30 had the same or similar X-ray powder diffraction patterns, DSC patterns, and TGA patterns (not shown) as the samples of Examples 28, indicating that the samples of Examples 29 to 30 were the same as the samples of Example 28. Substance.

Example 31

At room temperature, 520.0 mg of Ringer's 4 Bow Salt Form A prepared by the present invention was dissolved in 10.4 mL of dimethyl sulfoxide, and 84.0 mL of water was added thereto with stirring, and stirred for 16 hours to precipitate a white solid, and filtered, 40°. C was vacuum dried overnight to obtain 382.3 mg of white licylide 4 salt crystal form B, yield 73.5%.

The X-ray powder diffraction pattern of the calcium salt crystal form B is shown in Fig. 23.

The PLM spectrum of the calcium salt form B is shown in Figure 24 and is shown as a very fine irregular crystal.

The DSC spectrum of the calcium salt crystal form B is shown in Fig. 25, which shows a broad endothermic peak (melting peak) at 170 to 220 °C. The TGA spectrum of the calcium salt form B is shown in Figure 26, showing a weight loss of about 1.0% before 150 °C. The isothermal adsorption curve of the calcium salt form B is shown in Fig. 27, showing a weight change of about 0.4% in the range of 20% to 80% relative humidity.

The above test results show that: Lige Saidi 4 bow salt crystal form B has a crystalline state and has good physical properties such as low moisture absorption and high decomposition temperature.

Example 32

At room temperature, take 100.Omg of Ringer's 4 Bow Salt Form A prepared by the present invention, add 2.5 mL of dimercaptosulfoxide to dissolve, add 12.5 mL of water with stirring, stir for 5 hours, precipitate a white solid, filter, 40 After drying at 0<0>C under vacuum overnight, <RTI ID=0.0>>

Example 33

At room temperature, take 100.Omg of Ringer's 4 Bow Salt Form A prepared by the present invention, add 1.7 mL of dimethyl sulfoxide dissolved, add 17 mL of water with stirring, stir for 24 hours, precipitate a white solid, filter, 40 ° C was vacuum dried overnight to obtain 53.2 mg of a white calcium salt crystal form B, yield 53.2%.

The samples prepared in Examples 32 to 33 had the same or similar X-ray powder diffraction patterns, DSC patterns and TGA patterns (not shown) as the samples of Examples 31, indicating that the samples of Examples 32 to 33 were identical to the samples of Example 31. Substance.

Example 34

The amorphous Ringer Sodium salt prepared in Comparative Example 1, the Ringeride diethylamine salt crystal form B prepared by the present invention, and the Ringer's 4 Bow Salt Crystal Form B were subjected to light and oxidation for 0 days, 1 Day and 5 days stability experiments. The illumination conditions were 45001 x ± 5001 x illuminance and the oxidation conditions were a dryer equipped with urea hydrogen peroxide. The results are shown in Table 1.

Table 1 Stability data of the Ringside salt type

According to the data in Table 1, it is known that the purity of the Ligeridin sodium salt is lowered under the conditions of oxidation for 5 days. 34.58%, while the purity of the Ringer's calcium salt form B of the present invention was only reduced by 10.83%, and the purity of the Ringer's diethylamine salt form B of the present invention was only reduced by 8.95%. Under the condition of 5 days of illumination, it is known that the purity of the Ringer Sodium salt is reduced by 11.98%, while the purity of the Ringer's calcium salt form B of the present invention is only reduced by 2.19%. The present invention is the strength of the game. The purity of the amine salt Form B was only reduced by 3.19%.

Therefore, the Ringer's 4 Bow Salt Form B and the Ringer's Diethylamine Salt Form B of the present invention are significantly more stable to oxidation and light than the known Ringer Sodium salt.

Example 35

Tablets of the present application of Ringeride diethylamine salt are prepared, and the formulation is shown in Table 2.

Table 2 Tablet Formulation of Ringeride Diethylamine Salt

格格赛di diethylamine salt 290

Lactose 272

Copolyvidone 20

Crosslinked polyvinylpyrrolidone 10

Magnesium stearate 8

Tablet weight 600

Preparation steps:

(1) Screening of ligastide diethylamine salt, lactose, copolyvidone, and cross-linked polyvinylpyrrolidone.

(2) After sieving magnesium stearate, it is mixed with the mixture obtained in (1).

(3) The mixture obtained in (2) was compressed into tablets on a rotary tableting machine.

Note: The above-mentioned Ringer's diethylamine salt may be in the form of crystal form A, form B or form C.

Example 36

The tablets of the present application of Ringer's 4 bow salt are prepared, and the formulation is shown in Table 3.

Table 3 Tablet Formulation of Ringer's Salt

Dosage (mg)

Component

250

Lige Saide Calcium Salt 261

Lactose 301

Copolyvidone 20

Crosslinked polyvinylpyrrolidone 10

Magnesium stearate 8 Tablet weight 600

Preparation steps:

(1) Screening of Ringer's 4 bow salt, lactose, copolyvidone, and cross-linked polyvinylpyrrolidone.

Note: The above Ringer's 4 bow salt can be either Form A or Form B.

Example 37

Prepare a sterile powder of the Liguestatin diethylamine salt of the present application, and the formulation is shown in Table 4.

Table 4 Sterile powder formula of Ringeride diethylamine salt

Dosage (mg)

250

格格赛di diethylamine salt 290

Mannitol 15~60

Sodium sulfite 2.5-5

Sterile powder weight 307.5-355

Preparation steps:

(1) Take mannitol 15~60mg, sodium sulfite 2.5~5mg, add 2mL water for injection, stir at 25 °C ~ 100 °C for 10 ~ 60 minutes, filter, and reserve for use.

(2) Take 290mg of Ringer's diethylamine salt and add it to the solution of (1), add water for injection to 3~5mL, adjust the pH value to 8 by sodium hydroxide, filter it sterilely, and fill it into the vial. Semi-press plug, freeze-dried, sterile full plug, pressed aluminum cap, package.

Note: The above-mentioned Ringer's diethylamine salt may be in the form of crystal form A, form B or form C. The foregoing is only a specific embodiment of the present application, but the scope of protection of the present application is not limited thereto, and any person skilled in the art can change without thinking of creative work within the technical scope disclosed by the present application. Replacement should be covered by the scope of this application. All patent documents and non-patent publications cited in the present specification are hereby incorporated by reference in their entirety.

Claims

Rights request

1. The structural formula is as follows: diethylamine salt:

A method of producing a ligastide diethylamine salt according to claim 1, wherein the preparation method employs any one of the following two methods:

(1) forming a solution of Ringer's free acid in a soluble solvent, adding a diethylamine liquid to form a slurry and stirring, and concentrating the slurry to dryness to obtain the Ringeride diethylamine salt;

Preferably, the soluble solvent is selected from the group consisting of an alcohol or a ketone, preferably a d-C ₃ alcohol or a C ₃ -C ₄ ketone, more preferably ethanol or acetone;

Preferably, the molar ratio of the Riggside free acid to diethylamine is 1:1 to 1:10, preferably 1:2 to 1:5; preferably, the preparation temperature is room temperature, the slurry The stirring time is 10 to 24 hours, preferably 10 to 16 hours;

Preferably, the concentration of the Ringer's free acid in the soluble solvent is 10 to 50 mg/mL, preferably the concentration of the Ringer's free acid in the alcohol solvent is 10 to 25 mg/mL, preferably The concentration of the Ringer's free acid in the ketone solvent is 16-50 mg/mL;

(2) placing the ligastide free acid in an environment filled with diethylamine gas to obtain a ligastide diethylamine salt;

3. The Ringeride diethylamine salt according to claim 1, wherein the Ringer's diethylamine salt is a crystal form B of Ringer's diethylamine salt, which is represented by a diffraction angle of 2 Θ The X-ray powder diffraction pattern has the following characteristic peaks: 4·4±0·2°, 10·2±0·2°, 11·7±0·2°, 13·0±0·2°, 20· 9±0·2° and 23·4±0·2°.

4. The Ringeride diethylamine salt crystal form according to claim 3, wherein the X-ray powder diffraction pattern of the Ringer's diethylamine salt crystal form is represented by a diffraction angle of 2? It has the following characteristic peaks: 4·4±0·2°, 10·2±0·2°, 11·7±0·2°, 12·7±0·2°, 13·0±0·2°, 13·9±0·2°, 16·4±0·2°, 16·8±0·2°, 17·5±0·2°, 19·6±0·2°, 20·9±0 · 2° and 23·4±0·2°.

5. The Ringeride diethylamine salt crystal form according to claim 4, wherein said force grid race The X-ray powder diffraction pattern of the di-diethylamine salt crystal form B represented by the diffraction angle 2 具有 has the following characteristic peaks and their relative intensities:

2Θ Relative strength%

4.4 ± 0.2° 37.2

10.2 ± 0.2° 100.0

11.7 ± 0.2 ° 68.0

12.7 ± 0.2. 43.2

13.0 ± 0.2. 88.7

13.9 ± 0.2° 46.1

16.4 ± 0.2. 43.4

16.8 ± 0.2° 40.0

17·5±0·2° 38.9

18.2 ± 0.2° 30.7

18.5 ± 0.2. 27.2

19.6 ± 0.2. 50.9

19.9 ± 0.2° 24.3

20.9 ± 0.2. 62.7

22.1 ± 0.2 ° 33.0

22.7 ± 0.2. 32.2

23.4 ± 0.2. 87.6

24.1 ± 0.2° 50.0

24.3 ± 0.2 ° 36.7

24.6 ± 0.2. 29.5

26.1 ± 0.2. 53.2.

6. The method for preparing a crystalline form of the Ringeride diethylamine salt according to any one of claims 3 to 5, comprising the steps of: the force test obtained by the preparation method according to claim 2 Didiethylamine salt is placed in an environment having a relative humidity of 75% to 85% to obtain a crystalline form of ligastide diethylamine salt;

Preferably, the standing temperature is room temperature, and the standing time is 2 to 3 days, preferably 2 days;

Preferably, the relative humidity is 85%.

The use of the Ringeride diethylamine salt according to claim 1, wherein the Ringeride diethylamine salt is a crystal form A of Ringeride diethylamine salt, which is represented by a diffraction angle of 2Θ The X-ray powder diffraction pattern has the following characteristic peaks: 4.3 ± 0.2°, 11.2 ± 0.2°, 16.2 ± 0.2°, 17.0 ± 0.2°, 20.3 ± 0.2°, and 22.5 ± 0.2°.

8. The crystalline form A of Ringer's diethylamine salt according to claim 7, wherein the X-ray powder diffraction pattern of the Ringer's diethylamine salt crystal form A is represented by a diffraction angle of 2? The following characteristic peaks: 4.3 ± 0.2 °, 11.2 ± 0.2 °, 11.5 ± 0.2 °, 12.1 ± 0.2 °, 13.5 ± 0.2 °, 14.2 ± 0.2 °, 16.0 ± 0.2 °, 16.2 ± 0.2 °,

17.0 ± 0·2°, 19.9 ± 0·2°, 20·3 ± 0·2° and 2·5 ± 0·2°.

9. The Ringeride diethylamine salt crystal form according to claim 8, wherein the X-ray powder diffraction pattern of the Ringer's diethylamine salt crystal form A is represented by a diffraction angle of 2? The following characteristic peaks and their relative intensities:

2Θ Relative strength%

4.3 ± 0.2 ° 79.0

11.2 ± 0.2 ° 84.7

11.5 ± 0.2. 43.1

12.1 ± 0.2 ° 39.5

13·5±0·2° 25.2

14.2 ± 0.2° 30.3

16.0 ± 0.2. 43.9

16.2 ± 0.2 ° 60.8

17.0 ± 0.2. 100.0

18.9 ± 0.2° 15.7

19.9 士 0.2° 31.8

20.3 ± 0.2 ° 66.5

22.5 ± 0.2 ° 86.5

22.8 ± 0.2. 38.8

23.6 ± 0.2. 17.3

23.9 ± 0.2. 59.4

24.2 ± 0.2. 27.1

25.3 ± 0.2. 47.0

26.1 ± 0.2. 26.1.

The method for preparing the crystalline form of the Ringeride diethylamine salt according to any one of claims 7 to 9, characterized in that it comprises the following steps: The force test obtained by the preparation method according to claim 2 The didiethylamine salt is placed in an environment having a relative humidity of 92% to 97% to obtain the crystal form A of the Ringeride diethylamine salt;

Preferably, the standing temperature is room temperature, and the standing time is 1 to 4 days, preferably 1 to 2 days;

Preferably, the relative humidity is 92%.

11. The Ringeride diethylamine salt according to claim 1, wherein: the Ringeride diethylamine salt is a crystal form C of Ringeride diethylamine salt, which is represented by a diffraction angle of 2 Θ The X-ray powder diffraction pattern has the following characteristic peaks: 7.1 ± 0.2°, 11.3 ± 0.2°, 12.5 ± 0.2°, 17.7 ± 0.2°, 18.7 ± 0.2°, and 20.0 ± 0.2°.

12. The crystalline form C of Ringeride diethylamine salt according to claim 11, wherein the X-ray powder diffraction pattern of the Ringer's diethylamine salt crystal form C is represented by a diffraction angle of 2 Θ Has the following characteristic peaks: 7.1 ± 0.2 °, 9.4 ± 0.2 °, 11.3 ± 0.2 °, 11.7 ± 0.2 °, 12.5 ± 0.2 °, 17.2 ± 0.2 °, 17.7 ± 0.2 °, 18.7 ± 0.2 °,

20.0 ± 0·2°, 21.8 ± 0·2°, 23.1 ± 0.2° and 24.1 ± 0·2°.

13. The crystalline form C of Ringer's diethylamine salt according to claim 12, wherein the X-ray powder diffraction pattern of the Ringerite diethylamine salt crystal form C is represented by a diffraction angle of 2? The following characteristic peaks and their relative intensities:

2Θ Relative strength%

7· 1±0·2° 100.0

9.4 ± 0.2° 13.8

11.3 ± 0.2. 20.5

11.7 ± 0.2. 12.0

12.5 ± 0.2° 30.7

14.4 士 0.2° 7.0

15.6 ± 0.2 ° 6.5

17.2 ± 0.2° 15.4

17.7 ± 0.2. 18.7

18.7 ± 0.2 ° 22.3

20.0 ± 0.2. 18.7

20.7 ± 0.2. 9.4

21.1 ± 0.2. 12.3

21·5±0·2° 12.5

21.8 ± 0.2 ° 21.1

22.7 ± 0.2. 13.9

23.1 ± 0.2 ° 24.6

23.6 ± 0.2. 10.9

24.1 ± 0.2 ° 27.7

24.4 ± 0.2. 17.3.

The method for preparing the crystal form of the Ringeride diethylamine salt according to any one of claims 11 to 13, wherein the preparation method comprises the following steps: obtaining the preparation method according to claim 2 The Aggregate diethylamine salt is added to the organic solvent to stir and crystallize, wherein the organic solvent is selected from the group consisting of an ester, a ketone or a mixture thereof to obtain the crystal form C of the Ringeride diethylamine salt;

Preferably, the organic solvent is a C ₄ -C ₅ ester or a C ₃ -C ₄ ketone, preferably ethyl acetate or acetone; preferably, the crystallization temperature is room temperature, and the crystallization time is 0.5 to 16 hours, preferably 0.5~8 hours; Preferably, the mass to volume ratio of the Ringeride diethylamine salt to the organic solvent is 20 mg to 80 mg: 1 mL, preferably 50 mg to 80 mg: 1 mL.

15. The structure of Ringer's 4 丐 salt as shown below:

16. The method for preparing a Ringer's 4 bow salt according to claim 15, comprising the steps of: forming a solution of ligastide free acid in a soluble solvent, adding calcium hydroxide to form a slurry and stirring, Separating the solid, washing with water, and drying to obtain the Ringer's 4 bow salt;

Preferably, the molar ratio of the ligastide free acid to the calcium hydroxide is 1:0.5 to 1:2, preferably 1: 1.1-1: 1.5;

Preferably, the soluble solvent is selected from the group consisting of a ketone or an alcohol, preferably a C ₃ -C ₄ ketone or a d-C ₃ alcohol, more preferably acetone or ethanol;

Preferably, the temperature of the slurry is room temperature, and the stirring time of the slurry is 10 to 24 hours, preferably 10 to 16 hours;

Preferably, the concentration of the ligastide free acid in the soluble solvent is 10 to 50 mg/mL, and preferably the concentration of the ligastide free acid in the ketone solvent is 10 to 50 mg/mL, more preferably 10~20 mg/mL; Preferably, the concentration of the ligastide free acid in the alcohol solvent is 10-20 mg/mL.

The Ringer's 4 bow salt according to claim 15, wherein the Ringer's 4 bow salt is a Ringer's 4 bow salt crystal form A, which is represented by a diffraction angle of 2 X X- The ray powder diffraction pattern has the following characteristic peaks: 4.5 ± 0.2°, 8.6 ± 0.2°, 10.3 ± 0.2°, 13.5 ± 0.2°, 20.2 ± 0.2°, and 20.4 ± 0.2°.

The force of the Ringer's 4 salt crystal form A according to claim 17, wherein the X-ray powder diffraction pattern of the Ringer's calcium salt crystal form A represented by the diffraction angle 2 具有 has the following characteristic peaks. : 4.5±0.2°, 8.6 ± 0.2°, 9.0 ± 0·2°, 10·3±0·2°, 13.2 ± 0·2°, 13.5 ± 0·2°, 14.1 ± 0·2°, 17.3 0·2°, 18.7 ± 0·2°, 20.2 ± 0.2°, 20.4 ± 0.2° and 24.0 ± 0.2°.

The force of the Ringer's 4 salt crystal form according to claim 18, wherein the X-ray powder diffraction pattern of the Ringer's calcium salt crystal form represented by a diffraction angle of 2 具有 has the following characteristic peaks. And its relative strength:

2Θ Relative strength%

4.5 士 0.2 ^C 58.3

8.6 ± 0.2 ^C 33.9

9.0 ± 0.2 ^C 37.1

10·3±0·2 42.3

13.2 ± 0.2 37.1

13·5±0·2 67.2

14.1 ± 0.2 38.7

14.6 ± 0.2 26.4

15.9士 0.2 24.4

17·3±0·2 29.8

18.7 ± 0.2 37.6

20.2 ± 0.2 78.2

20.4 ± 0.2 100.0

24.0 ± 0.2 52.4

24.5 ± 0.2 30.1

27.0 ± 0.2 15.5

29.0 ± 0.2 19.9

29.4 ± 0.2 15.7

The method for producing the Ringer's 4 arc salt crystal form according to any one of claims 17 to 19, which comprises the step of: producing the force of the preparation method according to claim 16 4 Bow salt is stirred in water to obtain the Ringer's salt crystal form A;

Preferably, the mass to volume ratio of the Ringer's 4 bow salt to water is 5 mg to 10 mg: 1 mL, preferably 5 mg to 8 mg: 1 mL;

Preferably, the stirring temperature is room temperature, and the stirring time is 24 to 72 hours, preferably 24 to 36 hours.

The use of Ringer's 4 bow salt according to claim 15, wherein: the Ringer's 4 bow salt is a Ringer's 4 丐 salt crystal form B, which is represented by a diffraction angle of 2 的 X- The ray powder diffraction pattern has the following characteristic peaks: 10·2±0·2°, 13.3±0·2°, 18·2±0·2°, 18.8±0·2°, 19·8±0·2° and 20.6 ± 0 · 2 °.

The force of the Ringer's 4 salt crystal form according to claim 21, wherein the X-ray powder diffraction pattern of the Ringer's calcium salt crystal form having a diffraction angle of 2 具有 has the following characteristic peaks : 8.4 ± 0.2 °, 10.2 ± 0.2 °, 11.5 ± 0.2 °, 13.3 ± 0.2 °, 14.4 ± 0.2 °, 14.8 ± 0.2 °, 18.2 ± 0.2 °, 18.8 ± 0.2 °, 19.8 ± 0.2 °, 20.6 ± 0.2 ° , 23.2 ± 0.2 ° and 25.3 ± 0.2 °.

The force of the Ringer's 4 salt crystal form according to claim 22, wherein the X-ray powder diffraction pattern of the Ringer's calcium salt crystal form having a diffraction angle of 2 具有 has the following characteristic peaks And its relative strength: relative strength%

8.4 ± 0.2 ^C 11.7

10.2 ± 0.2 28.9

11·5±0·2 18.8

13·3±0·2 40.1

13.9 ± 0.2 17.0

14.4 ± 0.2. 18.9

14.8 ± 0.2° 23.5

18.2 ± 0.2 ° 25.0

18.8 ± 0.2° 55.7

19.4 ± 0.2. 21.4

19.8 ± 0.2 ° 44.8

20.6 ± 0.2. 100.0

21.5 ± 0.2. 25.3

21.9 ± 0.2° 32.4

23.2 ± 0.2. 44.9

23.9 ± 0.2. 35.6

25.3 ± 0.2. 76.4

25.9 ± 0.2. 39.7

27.9 ± 0.2. 37.0

The method for producing the force of the Ringer's 4 salt crystal form B according to any one of claims 21 to 23, comprising the steps of: the method of producing the method according to claim 20 4 Bow salt crystal form A is dissolved in dimercapto sulfoxide, and water is added to crystallize to obtain the Ringer's 4 bow salt crystal form B;

Preferably, the volume ratio of the dimercapto sulfoxide to water is 1:5 to 1:10, preferably 1:5 to 1:8; preferably, the Ringer's 4 丐 salt crystal form A is The concentration in the dimercaptosulfoxide is 40-60 mg/mL, preferably 40-50 mg/mL;

Preferably, the crystallization temperature is room temperature, and the crystallization time is 5 to 24 hours, preferably 5 to 16 hours.

25. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises a therapeutically and/or prophylactically effective amount of one or more pharmaceutically active ingredients selected from the group consisting of the Ringeride diethylamine salt of claim 1. The use of the Ringerdine diethylamine salt crystal form according to any one of claims 3 to 5, according to any one of claims 7 to 9, wherein the Ringerdidiamine salt crystal form A, claims 11 to 13 The crystal form of the Ringeride diethylamine salt according to any one of the above, the Ringer's 4 bow salt according to claim 15, the Ringer's 4 bow salt crystal form according to any one of claims 17 to 19. A. The Ringer's 4 Bow Salt Form B of any one of claims 21 to 23, and at least one pharmaceutically acceptable carrier.

The use of the Ringeride diethylamine salt according to claim 1, the Ringer's diethylamine salt crystal form B according to any one of claims 3 to 5, and the method of any one of claims 7 to 9. Ringerdidiamine salt crystal form A, Ringer's diethylamine salt form C according to any one of claims 11 to 13, and Ringer's 4 bow salt according to claim 15, claim The force composition of the Ringer's 4 bow salt crystal form A according to any one of 17 to 19, the force of the Ringer's 4 bow salt crystal form B according to any one of claims 21 to 23, or the pharmaceutical composition according to claim 25. Use in the preparation of a medicament for treating and/or preventing a solid tumor disease; the solid tumor disease is selected from a hematological blood disease such as white Blood disease, myelodysplastic syndrome, lymphoma, pancreatic cancer, liver cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, stomach cancer, bladder cancer, prostate cancer, colorectal cancer, kidney cancer, esophageal cancer, biliary tract cancer, basal Cell carcinoma, head and neck cancer, melanoma or glioma, preferably the solid tumor disease is a solid tumor disease susceptible to treatment with a nucleotide analog chemotherapeutic agent.

27. A method of treating and/or preventing a solid tumor disease, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more pharmaceutically active ingredients selected from the group consisting of claim 1 Didiethylamine salt, the crystal form of the Ringeride diethylamine salt according to any one of claims 3 to 5, and the crystal form of the Ringeride diethylamine salt according to any one of claims 7-9 A. The force of the Ringeride diethylamine salt crystal form C according to any one of claims 11 to 13, the force of the Ringer's 4 salt of claim 15, and the force of any one of claims 17 to 19.格赛 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 The composition; the solid tumor disease is selected from the group consisting of a malignant blood disease such as leukemia, myelodysplastic syndrome, lymphoma, pancreatic cancer, liver cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, stomach cancer, bladder cancer, prostate cancer, knot Rectal cancer, kidney cancer, esophageal cancer, biliary tract cancer, basal cell carcinoma Head and neck cancer, melanoma or glioma, preferably the solid tumor disease is a solid tumor disease susceptible to treatment nucleotide analog chemotherapeutic agent.