CN113121568A - Salt of macrocyclic compound and preparation method thereof - Google Patents

Abstract

The invention discloses a salt of a macrocyclic compound and a preparation method thereof, the preparation method is simple, 3 salt compounds can be obtained, wherein, the sulfate crystal form I has excellent stability and good solubility, is more suitable for preparing clinical drugs, and can better ensure the safety and effectiveness of the drugs.

Description

Salt of macrocyclic compound and preparation method thereof

Technical Field

The invention relates to the field of medicines, in particular to a salt of a macrocyclic compound and a preparation method thereof.

Background

The NTRK genes comprise NTRK1, NTRK2, and NTRK3, which are responsible for the synthesis of the family proteins, TRKA TRKB and TRKC, respectively, encoding Tropomyosin Receptor Kinase (TRK). Binding of neurotrophic factors to TRK proteins induces receptor dimerization, phosphorylation and activation of downstream signaling cascades of PI3K, RAS/MAPK/ERK and PLC-gamma.

Alterations in TRK signaling pathways, including gene fusion, protein overexpression, or single nucleotide alterations, have been found to be causative factors in many tumors, particularly fusion of NTRK genes, among the most well-defined ones, and the discovery that NTRK fusion proteins function as oncogenic drivers, promoting cancer cell growth and survival has led to the emergence of NTRK gene fusion as a new target for cancer therapy.

In 11 months in 2018, a first-generation drug LOXO-101 which can effectively treat 17 tumors and aims at patients with NTRK1/NTRK2/NTRK3 fusion is newly marketed in the United states, however, a part of cancer patients can generate drug resistance to the first-generation drug, and the drug resistance mutation of TRK kinase is one of the main reasons for generating the drug resistance, so that more effective drugs capable of overcoming the drug resistance of the first-generation drug need to be developed.

The compound A in the application is reported to be used for treating tumor diseases related to NTRK gene fusion, has the function of inhibiting protein kinase, and is expected to become a new second-generation medicament capable of overcoming the drug resistance of the first-generation medicament and applied to clinical treatment. In the case of preparing a medicament, the stability and solubility of the compound are particularly important, which guarantees the safety and effectiveness of the medicament, and therefore, the development of a more stable and more soluble salt crystal form is very necessary.

Disclosure of Invention

The invention mainly solves the technical problem of providing the sulfate of the macrocyclic compound, which has better stability and solubility than hydrochloride and fumarate.

In order to solve the technical problems, the invention adopts a technical scheme that:

providing a sulfate of a compound shown as a formula A, wherein the chemical ratio of the compound A to sulfuric acid is 1: 2-3;

further, the chemical ratio of the compound A to the sulfuric acid is 1: 2.

The invention also provides a sulfate of the compound shown as the formula A, wherein the chemical ratio of the compound A to sulfuric acid is 1: 2-3, the sulfate exists in a crystal form I, and Cu-Ka radiation is used to obtain an X-ray powder diffraction pattern, wherein the X-ray powder diffraction pattern at least comprises characteristic peaks located at 7.1 +/-0.2, 13.1 +/-0.2, 15.5 +/-0.2, 16.8 +/-0.2, 18.7 +/-0.2, 20.7 +/-0.2, 24.2 +/-0.2 and 25.8 +/-0.2 degrees 2 theta.

Further, the peak intensities of characteristic peaks at 7.1 ± 0.2, 13.1 ± 0.2, 15.5 ± 0.2, 16.8 ± 0.2, 18.7 ± 0.2, 20.7 ± 0.2, 24.2 ± 0.2, 25.8 ± 0.2 degrees 2 θ are about 71.9%, 35.4%, 66.0%, 52.6%, 83.5%, 98.4%, 81.0%, 100% in this order.

Further, the X-ray powder diffraction pattern also comprises characteristic peaks at 10.7 +/-0.2, 11.8 +/-0.2, 12.4 +/-0.2, 14.4 +/-0.2, 16.4 +/-0.2, 17.8 +/-0.2, 19.5 +/-0.2, 20.3 +/-0.2, 21.6 +/-0.2, 22.6 +/-0.2, 23.0 +/-0.2, 24.7 +/-0.2, 25.1 +/-0.2, 26.4 +/-0.2, 27.0 +/-0.2 and 28.1 +/-0.2 degrees 2 theta;

further, the peak intensities of characteristic peaks at 10.7 + -0.2, 11.8 + -0.2, 12.4 + -0.2, 14.4 + -0.2, 16.4 + -0.2, 17.8 + -0.2, 19.5 + -0.2, 20.3 + -0.2, 21.6 + -0.2, 22.6 + -0.2, 23.0 + -0.2, 24.7 + -0.2, 25.1 + -0.2, 26.4 + -0.2, 27.0 + -0.2, 28.1 + -0.2 degrees 2 theta are about 17.7%, 23.4%, 7.6%, 13.9%, 34.1%, 15.0%, 38.6%, 97.5%, 58.5%, 45.9%, 39.2%, 82.9%, 51.6%, 71.5%, 32.6%, 29.9% in this order;

further, the chemical ratio of the compound A to the sulfuric acid is 1: 2.

Further, the sulfate salt has an endothermic peak at 217. + -. 2 ℃ in differential scanning calorimetry.

The invention also provides a preparation method of the sulfate, which comprises the following steps: and mixing the compound A with tetrahydrofuran, mixing concentrated sulfuric acid, and separating out a solid after reaction.

In the specific embodiment of the invention, concentrated sulfuric acid is added into the system in a dropwise manner.

In a specific embodiment of the invention, the compound a is mixed with tetrahydrofuran, concentrated sulfuric acid is added into the mixture, and the mixture is stirred, filtered and rinsed with tetrahydrofuran to obtain the compound a.

Further, the compound a: the feed-liquid ratio of tetrahydrofuran is 15-18 mg: 1mL, preferably 16-17 mg: 1 mL; the compound A: the dosage ratio of concentrated sulfuric acid is 3.3-3.8 g: 1mL, preferably 3.5-3.6 g: 1 mL.

The invention also provides application of the sulfate in preparing TRK inhibitors and/or protein kinase inhibitors.

The compound A can be used as a TRK inhibitor and can be used for treating tumor diseases caused by NTRK gene fusion, and the compound A also has the effect of inhibiting the activity of protein kinase, can be used as a protein kinase inhibitor and can be used for treating TRK and related diseases mediated by protein kinase, so that the sulfate of the compound A can also be used for preparing medicines for treating TRK and related diseases mediated by protein kinase, the solubility and the stability of the sulfate are improved to a certain extent, and the compound A is more suitable for being applied to medicines.

The invention also provides a pharmaceutical composition which comprises the sulfate.

The invention also provides a hydrochloride of the compound shown as the formula A, wherein the chemical ratio of the compound A to the hydrochloric acid is 1: 1;

further, the hydrochloride exists in a form II, and an X-ray powder diffraction pattern obtained by using Cu-k alpha radiation at least comprises characteristic peaks positioned at 6.5 +/-0.2, 9.3 +/-0.2, 14.2 +/-0.2, 18.7 +/-0.2, 20.6 +/-0.2, 23.4 +/-0.2 and 25.5 +/-0.2 degrees 2 theta; further, the peak intensities of the characteristic peaks at 6.5 ± 0.2, 9.3 ± 0.2, 14.2 ± 0.2, 18.7 ± 0.2, 20.6 ± 0.2, 23.4 ± 0.2, 25.5 ± 0.2 degrees 2 theta are about 53.4%, 56.5%, 27.8%, 66.0%, 62.4%, 35.8%, 100% in sequence;

further, the X-ray powder diffraction pattern also comprises characteristic peaks at 12.6 +/-0.2, 13.0 +/-0.2, 15.9 +/-0.2, 17.5 +/-0.2, 18.1 +/-0.2, 19.6 +/-0.2, 20.1 +/-0.2, 21.2 +/-0.2, 21.8 +/-0.2, 22.3 +/-0.2, 22.4 +/-0.2, 26.2 +/-0.2, 27.2 +/-0.2 and 32.3 +/-0.2 degrees 2 theta; further, the peak intensities of characteristic peaks at 12.6 + -0.2, 13.0 + -0.2, 15.9 + -0.2, 17.5 + -0.2, 18.1 + -0.2, 19.6 + -0.2, 20.1 + -0.2, 21.2 + -0.2, 21.8 + -0.2, 22.3 + -0.2, 22.4 + -0.2, 26.2 + -0.2, 27.2 + -0.2, 32.3 + -0.2 degrees 2 theta are about 12.7%, 20.8%, 17.2%, 19.0%, 39.3%, 40.0%, 54.6%, 29.0%, 27.6%, 21.2%, 18.7%, 33.3%, 35.7%, 17.2% in this order;

further, the hydrochloride has endothermic peaks at 138 + -2 ℃ and 313 + -2 ℃ in differential scanning calorimetry; further, there is an exothermic peak at 202 ± 2 ℃;

furthermore, in thermogravimetric analysis of the hydrochloride, the weight loss is 120-170 +/-2 ℃.

The invention also provides fumarate of the compound shown as the formula A, wherein the chemical ratio of the compound A to the fumaric acid is 2: 1;

further, the fumarate exists in a form III, and an X-ray powder diffraction pattern obtained by using Cu-Ka radiation at least comprises characteristic peaks at 9.3 +/-0.2, 11.6 +/-0.2, 15.1 +/-0.2, 18.9 +/-0.2, 23.0 +/-0.2, 24.2 +/-0.2, 25.5 +/-0.2 and 30.7 +/-0.2 degrees 2 theta; further, the peak intensities of characteristic peaks at 9.3 ± 0.2, 11.6 ± 0.2, 15.1 ± 0.2, 18.9 ± 0.2, 23.0 ± 0.2, 24.2 ± 0.2, 25.5 ± 0.2, 30.7 ± 0.2 degrees 2 theta are about 67.0%, 14.6%, 12.3%, 80.1%, 100%, 58.9%, 36.0%, 18.4% in sequence;

further, the X-ray powder diffraction pattern also comprises characteristic peaks at 10.9 +/-0.2, 12.8 +/-0.2, 13.8 +/-0.2, 16.2 +/-0.2, 19.7 +/-0.2, 21.4 +/-0.2, 22.0 +/-0.2, 24.8 +/-0.2, 25.9 +/-0.2, 28.8 +/-0.2, 29.9 +/-0.2, 31.4 +/-0.2 and 34.4 +/-0.2 degrees 2 theta; further, the peak intensities of characteristic peaks at 10.9 ± 0.2, 12.8 ± 0.2, 13.8 ± 0.2, 16.2 ± 0.2, 19.77 ± 0.2, 21.4 ± 0.2, 22.0 ± 0.2, 24.8 ± 0.2, 25.9 ± 0.2, 28.8 ± 0.2, 29.9 ± 0.2, 31.4 ± 0.2, 34.4 ± 0.2 degrees 2 theta are about 11.8%, 6.8%, 6.3%, 6.8%, 19.8%, 15.5%, 20.3%, 9.1%, 17.8%, 10.0%, 11.2%, 9.4%, 9.8% in this order;

further, the fumarate has endothermic peaks at 134 + -2 ℃ and 317 + -2 ℃ in differential scanning calorimetry;

furthermore, in thermogravimetric analysis of the fumarate, weight loss is realized at 120-160 +/-2 ℃, and weight loss is continuously realized at 170-260 +/-2 ℃.

The invention has the beneficial effects that:

the invention provides various salts of a compound A, the preparation method is simple and easy to implement, wherein sulfate has better stability than amorphous, hydrochloride, fumarate and free alkali crystal form I, and has better solubility than the hydrochloride, fumarate and free alkali crystal form I, so that the compound A is more suitable for preparing clinical medicines and can better ensure the safety and effectiveness of the medicines.

Drawings

Figure 1 is an XRPD detection pattern of sulfate form I of the present invention;

FIG. 2 is a DSC/TGA survey of form I of the sulfate salt of the present invention;

figure 3 is an XRPD detection pattern of form II of the hydrochloride salt of the present invention;

figure 4 is a DSC/TGA detection profile of form II of the hydrochloride salt of the present invention;

FIG. 5 shows a comparison of hydrogen spectra of fumarate salt of this invention with Compound A (top: Compound A; bottom: fumarate salt);

FIG. 6 shows a comparison of hydrogen spectra of fumarate salt of this invention with Compound A (top: Compound A; bottom: fumarate salt);

figure 7 is an XRPD detection pattern of form III fumarate salt of the present invention;

FIG. 8 is a DSC/TGA assay diagram of form III fumarate salt of the present invention;

figure 9 is an amorphous XRPD detection pattern of compound a of the present invention;

FIG. 10 is a DSC/TGA chromatogram of the amorphous form of Compound A of the present invention;

figure 11 is an XRPD detection pattern of form I of the free base of the invention;

figure 12 is a DSC/TGA trace of form I of the free base of the present invention.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In the invention, X-ray powder diffraction (XRPD) analysis adopts Dx-2700BH, Cu target irradiation. The detection range is 3-40 degrees, the step length is 0.02 degree, and the speed is 0.2 s-step-1.

The synchronous thermal analyzer (TGA/DSC) of the invention is a Mettler-Toledo TGA/DSC analyzer³⁺. The rate of temperature rise of the apparatus was 10K/min.

The compound A in the invention can be synthesized by referring to the prior art or obtained by the market.

EXAMPLE 1 preparation of sulfate

5g of Compound A are dissolved in 300ml of tetrahydrofuran solution, to which 1.41ml of concentrated sulfuric acid are further added and stirred for 6 hours. Filtration and elution with tetrahydrofuran twice gave 4.7g of a white solid. The XRPD measurements are shown in fig. 1 and table 1 and are defined as sulfate form I. The DSC/TGA measurements (FIG. 2) showed that endothermic peaks appeared at 42. + -. 2 ℃ (onset), 70. + -. 2 ℃ (onset), 217. + -.2 ℃ (onset), and that there was a gradient weight loss before 100 ℃.

TABLE 1

Example 2 sulfate content titration

1. Preparing a solution:

a) preparation of BaCl₂Solution: weighing BaCl₂1219.20mg, placing in a 100ml volumetric flask, adding a proper amount of water, ultrasonically dissolving, diluting to a scale, and shaking up;

b) configuration of Na₂SO₄Solution: weighing BaCl₂712.32mg, placing in a 100ml volumetric flask, adding a proper amount of water, ultrasonically dissolving, diluting to a scale, and shaking up;

c) preparing an alizarin red indicator: weighing 100.36mg of alizarin red, placing the alizarin red into a 100ml volumetric flask, adding a proper amount of water, ultrasonically dissolving, diluting to a scale, and shaking up;

d) preparing a sulfate solution of compound a: 100.15mg and 103.16mg of sulfate prepared in example 1 were weighed and placed in 100ml beakers, respectively, and an appropriate amount of 20% ethanol was added thereto for ultrasonic dissolution, and labeled as sample solution 1 and sample solution 2.

2. Titration:

a) taking a sample solution 1, dripping 6-8 drops of indicator into the sample solution, and using BaCl₂After titration of the solution to endpoint, the time at which the solution was titrated with BaCl was recorded₂The volume of the solution is 3.50 ml; with Na₂SO₄Solution consumption titration consumes BaCl in the solution₂0.25ml of the total amount was used. The sulfuric acid content was calculated to be 2.28 equivalents.

b) Taking a sample solution 2, dripping 6-8 drops of indicator into the sample solution, and using BaCl₂After titration of the solution to endpoint, the time at which the solution was titrated with BaCl was recorded₂The volume of the solution is 3.61 ml; with Na₂SO₄Solution consumption titration consumes BaCl in the solution₂0.18ml of the total amount was used. The sulfuric acid content was calculated to be 2.13 equivalents.

The above experimental results can be used to estimate that: the raw material medicine contains 2 molecules of sulfuric acid.

EXAMPLE 3 preparation of the hydrochloride salt

5g of Compound A are dissolved in 300ml of tetrahydrofuran solution, to which 2.12ml of concentrated hydrochloric acid are further added and stirred for 6 hours. Vacuum concentrating to obtain white solid, adding isopropyl ether for dispersion, and filtering to obtain white solid 4.7 g. Confirmation of 1 equivalent of the hydrochloride salt was by potentiometric titration. The XRPD assay results are shown in figure 3 and table 2 and are defined as hydrochloride form II. DSC/TGA detection results (FIG. 4) showed that endothermic peaks appeared at about 138. + -. 2 ℃ (onset) and 313. + -. 2 ℃ (onset), and exothermic peaks appeared at 202. + -. 2 ℃ (onset); no obvious weight loss is caused before 100 ℃, and the weight loss is 10% at 120-170 +/-2 ℃.

TABLE 2

Characteristic peak: 6.5 +/-0.2 degrees; 9.3 +/-0.2 degrees; 14.2 +/-0.2 degrees; 18.7 +/-0.2 degrees; 20.6 +/-0.2 degrees; 23.4 +/-0.2 degrees; 25.5 +/-0.2 degrees;

preferred characteristic peaks further include: 12.6 +/-0.2 degrees; 13.0 plus or minus 0.2 degrees; 15.9 +/-0.2 degrees; 17.5 +/-0.2 degrees; 18.1 +/-0.2 degrees; 19.6 +/-0.2 degrees; 20.1 +/-0.2 degrees; 21.2 +/-0.2 degrees; 21.8 +/-0.2 degrees; 22.3 +/-0.2 degrees; 22.4 +/-0.2 degrees; 26.2 +/-0.2 degrees; 27.2 +/-0.2 degrees; 32.3 +/-0.2 degrees.

EXAMPLE 4 preparation of fumarate salt

5g of Compound A was dissolved in 300ml of a tetrahydrofuran solution, and 2.94g of fumaric acid was further added thereto, and stirred for 6 hours. Concentrating under reduced pressure to obtain solid, dispersing with isopropyl ether, filtering to obtain white solid, and recrystallizing with 5ml methanol to obtain 450mg white solid.

¹H NMR(400MHz,DMSO-d₆): the results show that the fumarate salt has two more peaks relative to the free base: δ 6.62-6.63(2H, s), δ 13.0-13.3(2H, s). The peak areas (fig. 5 and 6) show that: 2 molecules of the compound A and 1 molecule of fumaric acid form salt. The XRPD assay results are shown in fig. 7 and table 2, and are defined as fumarate form III. DSC/TGA detection result (FIG. 8) shows that endothermic peaks appear at 134. + -. 2 ℃ (onset), 317. + -. 2 ℃ (onset); no obvious weight loss is caused before 100 ℃, the weight loss is 4.9 percent at 120-160 +/-2 ℃ and the continuous weight loss is 13.6 percent at 170-260 +/-2 ℃.

TABLE 3

Characteristic peak: 9.3 +/-0.2 degrees; 11.6 +/-0.2 degrees; 15.1 +/-0.2 degrees; 18.9 +/-0.2 degrees; 23.0 +/-0.2 degrees; 24.2 +/-0.2 degrees; 25.5 +/-0.2 degrees; 30.7 +/-0.2 degrees;

preferred characteristic peaks further include: 10.9 +/-0.2 degrees; 12.8 +/-0.2 degrees; 13.8 +/-0.2 degrees; 16.2 +/-0.2 degrees; 19.77 +/-0.2 degrees; 21.4 +/-0.2 degrees; 22.0 +/-0.2 degrees; 24.8 +/-0.2 degrees; 25.9 +/-0.2 degrees; 28.8 +/-0.2 degrees; 29.9 ± 0.2 °; 31.4 +/-0.2 degrees; 34.4 +/-0.2 degrees.

EXAMPLE 5 preparation of free base amorphous form

After 5g of compound a was dissolved in 50ml to 80ml of a mixed solvent of DCM and MeOH (V: V ═ 4: 6 to 6: 4), the mixture was concentrated under reduced pressure in a water bath at 45 ℃. A translucent solid was obtained. The XRPD assay result (fig. 9) obtained was amorphous. The DSC/TGA measurement (FIG. 10) showed that an exothermic peak appeared at around 170. + -. 2 ℃ C. (onset) and an endothermic peak appeared at 322. + -. 2 ℃ C. (onset).

Example 6 preparation of free base form I

Taking 30mg of amorphous compound A, placing the amorphous compound A in a brown glass bottle, adding 0.5ml of diethyl ether into the glass bottle, dispersing the amorphous compound A, and stirring the mixture at room temperature for 48 hours under sealed conditions to obtain powdery solid. The XRPD measurements are shown in figure 11 and table 4 and are defined as form I of the free base. The DSC/TGA profile shows (fig. 12) that an endothermic peak appears at 322 ± 2 ℃ (onset) for form I of the free base and the sample begins to melt.

TABLE 4

Example 7

Stability comparison of salts of the invention:

table 5 stability effect data for sulfate form I

Table 6 stability effect data for hydrochloride form II

Table 7 fumarate salt form III stability effect data

Table 8 free base form I stability effect data

TABLE 9 free base amorphous stability Effect data

As can be seen from tables 5 to 9, under the condition of keeping out of the sun, the stability of the sulfate crystal form I is superior to that of hydrochloride, fumarate, free alkali crystal form I and free alkali amorphous form. Under the normal condition, for the medicine which is not stable enough under the illumination condition, dark color sealing package is directly adopted to realize the light-proof dry storage, but in the transportation process of the medicine, the environmental temperature may be higher than the conventional room temperature, and the sulfate crystal form I can keep the optimal stability under the condition of keeping out light at 60 ℃, thereby being more suitable for the actual production application.

Solubility comparisons of salts of the invention:

watch 10

The data in table 10 show that the solubility of the sulfate of the present invention is significantly better than that of the free base form I, and at the same time, the hydrochloride and fumarate salts, and in practical pharmaceutical applications, stability and solubility need to be considered, and the sulfate of the present invention has a combined advantage in solubility and stability.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (11)

1. The sulfate of the compound shown as the formula A is characterized in that the chemical ratio of the compound A to sulfuric acid is 1: 2-3;

2. the sulfate of claim 1, wherein the chemical ratio of compound a to sulfuric acid is 1: 2.

3. The sulfate of the compound shown in the formula A is characterized in that the chemical ratio of the compound A to sulfuric acid is 1: 2-3, the sulfate exists in a crystal form I, Cu-Ka radiation is used, and an X-ray powder diffraction pattern obtained at least comprises characteristic peaks located at 7.1 +/-0.2, 13.1 +/-0.2, 15.5 +/-0.2, 16.8 +/-0.2, 18.7 +/-0.2, 20.7 +/-0.2, 24.2 +/-0.2 and 25.8 +/-0.2 degrees 2 theta;

4. the sulfate salt of claim 3, further comprising characteristic peaks in the X-ray powder diffraction pattern at 10.7 ± 0.2, 11.8 ± 0.2, 12.4 ± 0.2, 14.4 ± 0.2, 16.4 ± 0.2, 17.8 ± 0.2, 19.5 ± 0.2, 20.3 ± 0.2, 21.6 ± 0.2, 22.6 ± 0.2, 23.0 ± 0.2, 24.7 ± 0.2, 25.1 ± 0.2, 26.4 ± 0.2, 27.0 ± 0.2, 28.1 ± 0.2 degrees 2 θ;

further, the chemical ratio of the compound A to the sulfuric acid is 1: 2.

5. The sulfate salt according to any one of claims 3 or 4, which has an endothermic peak at 217 ± 2 ℃ in differential scanning calorimetry.

6. The method for preparing sulfate according to any one of claims 1 to 5, comprising: and mixing the compound A with tetrahydrofuran, dropwise adding concentrated sulfuric acid, and separating out a solid after reaction.

7. The process according to claim 6, wherein the compound A: the feed-liquid ratio of tetrahydrofuran is 15-18 mg: 1mL, preferably 16-17 mg: 1 mL; the compound A: the dosage ratio of concentrated sulfuric acid is 3.3-3.8 g: 1mL, preferably 3.5-3.6 g: 1 mL.

8. Use of a sulfate salt according to any one of claims 1 to 5 in the preparation of a TRK inhibitor and/or a protein kinase inhibitor.

9. A pharmaceutical composition comprising the sulfate salt according to any one of claims 1 to 5.

10. The hydrochloride of the compound shown as the formula A is characterized in that the chemical ratio of the compound A to hydrochloric acid is 1: 1;

further, the hydrochloride exists in a form II, and an X-ray powder diffraction pattern obtained by using Cu-k alpha radiation at least comprises characteristic peaks positioned at 6.5 +/-0.2, 9.3 +/-0.2, 14.2 +/-0.2, 18.7 +/-0.2, 20.6 +/-0.2, 23.4 +/-0.2 and 25.5 +/-0.2 degrees 2 theta; further, the X-ray powder diffraction pattern also comprises characteristic peaks at 12.6 +/-0.2, 13.0 +/-0.2, 15.9 +/-0.2, 17.5 +/-0.2, 18.1 +/-0.2, 19.6 +/-0.2, 20.1 +/-0.2, 21.2 +/-0.2, 21.8 +/-0.2, 22.3 +/-0.2, 22.4 +/-0.2, 26.2 +/-0.2, 27.2 +/-0.2 and 32.3 +/-0.2 degrees 2 theta;

further, the hydrochloride has endothermic peaks at 138 + -2 ℃ and 313 + -2 ℃ in differential scanning calorimetry; further, there is an exothermic peak at 202 ± 2 ℃;

furthermore, in thermogravimetric analysis of the hydrochloride, the weight loss is 120-170 +/-2 ℃.

11. The fumarate of the compound shown as the formula A is characterized in that the chemical ratio of the compound A to fumaric acid is 2: 1;

further, the fumarate exists in a form III, and an X-ray powder diffraction pattern obtained by using Cu-Ka radiation at least comprises characteristic peaks at 9.3 +/-0.2, 11.6 +/-0.2, 15.1 +/-0.2, 18.9 +/-0.2, 23.0 +/-0.2, 24.2 +/-0.2, 25.5 +/-0.2 and 30.7 +/-0.2 degrees 2 theta;

further, the X-ray powder diffraction pattern also comprises characteristic peaks at 10.9 +/-0.2, 12.8 +/-0.2, 13.8 +/-0.2, 16.2 +/-0.2, 19.7 +/-0.2, 21.4 +/-0.2, 22.0 +/-0.2, 24.8 +/-0.2, 25.9 +/-0.2, 28.8 +/-0.2, 29.9 +/-0.2, 31.4 +/-0.2 and 34.4 +/-0.2 degrees 2 theta;

further, the fumarate has endothermic peaks at 134 + -2 ℃ and 317 + -2 ℃ in differential scanning calorimetry;

furthermore, in thermogravimetric analysis of the fumarate, weight loss is realized at 120-160 +/-2 ℃, and weight loss is continuously realized at 170-260 +/-2 ℃.

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