Salt and crystal form of pharmaceutical intermediate, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a salt and a crystal form of a pharmaceutical intermediate, and a preparation method therefor and a use thereof. The present invention provides a salt of a compound as represented by formula (II), and a maleate crystal form A, a mesylate crystal form A, a gentisate crystal form A, and a tartrate crystal form A thereof. The crystal forms provided in the present invention are all anhydrous crystal forms, and has high crystallinity, good stability, resistance to high temperature and high humidity, and low hygroscopicity.

Description

Salt, crystal form of a pharmaceutical intermediate, and preparation method and application thereof

[0001] This application claims priority to Chinese patent application 2024104641959 with a filing date of April 17, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to a salt, crystal form of a pharmaceutical intermediate, and preparation method and application thereof, in particular to a salt of a compound of formula (II) and a preparation method thereof. BACKGROUND

[0003] SARS-CoV-2 belongs to single positive strand RNA virus, and has high homology with SARS-CoV and MERS-CoV. After the virus infects into the host cell, with the help of the host cell, its genetic material RNA is first translated to express two polyprotein precursors (pp1a and pp1ab), which are intramolecularly cleaved by 3CL protease and PL protease to produce multiple non-structural proteins. Since 3CL protease is responsible for cleavage at least at 11 sites, it is also called main protease (Mpro). Non-structural proteins are involved in the production of viral subgenomic RNA and four structural proteins (E protein, M protein, S protein and N protein), and then complete the propagation and release of progeny virus; 3CL protease belongs to cysteine protease, and the active form is a homodimer. 3CL protease is relatively conserved in coronavirus, and the substrates of 3CL proteases of different coronaviruses have common characteristics; since there is no protease homologous to 3CL protease in the human body, 3CL protease becomes one of the ideal anti-coronavirus targets.

[0004] Developing drugs that can effectively resist coronavirus is currently needed in clinical drug use. Patent PCT / CN2022 / 087511 found a 3CL protease inhibitor with good anti-coronavirus activity. In order to further improve the accessibility of the drug and be more conducive to scale-up production, it is necessary to develop new methods for obtaining intermediates of the 3CL protease inhibitor, including the accessibility of reagents and raw materials, strengthening cost control, improving the degree of scale-up production, ensuring process production safety, etc. The molecular structure of the 3CL protease inhibitor is as follows: SUMMARY

[0005] In view of the problems in the prior art in preparing 3CL protease inhibitors, the present application provides a compound intermediate of formula (II) or a pharmaceutically acceptable salt thereof, a crystal form thereof, a preparation method thereof and an application thereof. The intermediate compound of the present application has high crystallinity, good stability, high temperature resistance, high humidity resistance, low hygroscopicity, high product purity and high yield.

[0006] The present application solves the above technical problems by the following technical solutions.

[0007] The present application provides a salt of the compound of formula (II), which is a maleate salt, a mesylate salt, a gentisate salt or a tartrate salt.

[0008] Preferably, the molar ratio of maleic acid, methanesulfonic acid, gentisic acid or tartaric acid to the compound of formula (II) is 1.1:1 or 1.0:1, more preferably 1.0:1.

[0009] The present application provides a crystal form A of the maleate salt of the compound of formula (II), which has an X-ray powder diffraction pattern expressed in 2θ using Cu-Kα radiation having diffraction peaks at the following positions: 10.37°±0.20°, 13.75°±0.20°, 14.77°±0.20°, 19.47°±0.20°, 20.97°±0.20°, 21.67°±0.20°.

[0010] In some embodiments of the present application, the X-ray powder diffraction pattern expressed in 2θ angle of the crystal form A of the maleate salt of the compound of formula (II) further has diffraction peaks at one or more of the following positions: 11.67°±0.20°, 17.48°±0.20°, 19.75°±0.20°, 22.79°±0.20°, 23.48°±0.20°, 25.23°±0.20°, 26.93°±0.20°, 28.07°±0.20°, 29.80°±0.20°, 32.89°±0.20°, 38.37°±0.20°.

[0011] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has an X-ray powder diffraction pattern, in terms of 2-theta, with diffraction peaks at 10.37°±0.20°, 11.67°±0.20°, 13.75°±0.20°, 14.77°±0.20°, 17.48°±0.20°, 19.47°±0.20°, 19.75°±0.20°, 20.97°±0.20°, 21.67°±0.20°, 22.79°±0.20°, 23.48°±0.20°, 25.23°±0.20°, 26.93°±0.20°, 28.07°±0.20°, 29.80°±0.20°, 32.89°±0.20°, 38.37°±0.20°.

[0012] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has an X-ray powder diffraction pattern with diffraction peaks as shown in the following table:

[0013] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has an X-ray powder diffraction pattern as shown in Figure 1.

[0014] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has an X-ray powder diffraction pattern obtained by the following parameters:

[0015] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has a differential scanning calorimetry curve (DSC) with an endothermic peak at 143.8±3.0°C (peak).

[0016] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has a differential scanning calorimetry curve (DSC) with a heat of fusion of the endothermic peak at 135.6-143.8°C of 89.25 J / g.

[0017] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has a differential scanning calorimetry curve as shown in Figure 2.

[0018] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has a thermogravimetric analysis curve (TGA) with a weight loss of 0.68% at 130.0°C.

[0019] In some embodiments of the application, Form A of the compound of formula (II) maleate salt has a thermogravimetric analysis curve as shown in Figure 2.

[0020] In some embodiments of the present application, the crystalline Form A of the compound of formula (II) maleate salt is obtained by the TGA and / or DSC pattern of the crystalline form as follows:

[0021] In some embodiments of the present application, the crystalline Form A of the compound of formula (II) maleate salt is an anhydrous crystalline form.

[0022] In some embodiments of the present application, the molar ratio of the compound of formula (II) to the maleic acid is 1.0:1.

[0023] The present application also provides a preparation method of the crystalline Form A of the compound of formula (II) maleate salt as described above, which comprises the following steps:

[0024] mixing the compound of formula (II) and the maleic acid in an organic solvent, and separating after stirring;

[0025] Preferably, the organic solvent is ethyl acetate.

[0026] Preferably, the molar ratio of the maleic acid to the compound of formula (II) is 1.05:1.

[0027] The present application provides a crystalline Form A of the compound of formula (II) methanesulfonate salt, which has X-ray powder diffraction pattern expressed in degrees 2θ using Cu-Kα radiation with diffraction peaks at the following positions: 7.23°±0.20°, 13.91°±0.20°, 16.36°±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.94°±0.20°;

[0028] In some embodiments of the present application, the crystalline Form A of the compound of formula (II) methanesulfonate salt has X-ray powder diffraction pattern expressed in degrees 2θ further having diffraction peaks at one or more of the following positions: 9.92°±0.20°, 12.39°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 23.21°±0.20°, 24.03°±0.20°.

[0029] In some embodiments of the application, Form A of the mesylate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2-theta, with diffraction peaks at 7.23° ± 0.20°, 9.92° ± 0.20°, 13.91° ± 0.20°, 16.36° ± 0.20°, 12.39° ± 0.20°, 17.85° ± 0.20°, 18.59° ± 0.20°, 18.95° ± 0.20°, 19.71° ± 0.20°, 20.65° ± 0.20°, 21.94° ± 0.20°, 23.21° ± 0.20°, 24.03° ± 0.20°.

[0030] In some embodiments of the application, Form A of the mesylate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2-theta, with further diffraction peaks at one or more of 10.35° ± 0.20°, 11.83° ± 0.20°, 14.66° ± 0.20°, 21.36° ± 0.20°, 22.87° ± 0.20°, 24.92° ± 0.20°, 25.27° ± 0.20°, 26.60° ± 0.20°, 27.30° ± 0.20°, 28.34° ± 0.20°.

[0031] In some embodiments of the application, Form A of the mesylate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2-theta, with diffraction peaks at 7.23° ± 0.20°, 9.92° ± 0.20°, 10.35° ± 0.20°, 11.83° ± 0.20°, 12.39° ± 0.20°, 13.91° ± 0.20°, 14.66° ± 0.20°, 16.36° ± 0.20°, 17.85° ± 0.20°, 18.59° ± 0.20°, 18.95° ± 0.20°, 19.71° ± 0.20°, 20.65° ± 0.20°, 21.36° ± 0.20°, 21.94° ± 0.20°, 22.87° ± 0.20°, 23.21° ± 0.20°, 24.03° ± 0.20°, 24.92° ± 0.20°, 25.27° ± 0.20°, 26.60° ± 0.20°, 27.30° ± 0.20°, 28.34° ± 0.20°.

[0032] In some embodiments of the application, the Form A crystalline form of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern, in terms of 2-theta, further comprising one or more of the following additional peaks: 8.23° ± 0.20°, 15.20° ± 0.20°, 22.57° ± 0.20°, 24.43° ± 0.20°, 26.32° ± 0.20°, 29.00° ± 0.20°, 29.40° ± 0.20°, 29.98° ± 0.20°, 31.23° ± 0.20°, 32.01° ± 0.20°, 32.75° ± 0.20°, 33.26° ± 0.20°, 34.60° ± 0.20°, 35.39° ± 0.20°, 36.55° ± 0.20°, 37.88° ± 0.20°, 38.44° ± 0.20°, 39.22° ± 0.20°.

[0033] In some embodiments of the application, the Form A crystalline form of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern, in terms of 2-theta, further comprising one or more of the following additional peaks: 8.23° ± 0.20°, 15.20° ± 0.20°, 22.57° ± 0.20°, 24.43° ± 0.20°, 26.32° ± 0.20°, 29.00° ± 0.20°, 29.40° ± 0.20°, 29.98° ± 0.20°, 31.23° ± 0.20°, 32.01° ± 0.20°, 32.75° ± 0.20°, 33.26° ± 0.20°, 34.60° ± 0.20°, 35.39° ± 0.20°, 36.55° ± 0.20°, 37.88° ± 0.20°, 38.44° ± 0.20°, 39.22° ± 0.20°.

[0034] In some embodiments of the application, the Form A crystalline form of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern, in terms of 2-theta, further comprising one or more of the following additional peaks: 8.23° ± 0.20°, 15.20° ± 0.20°, 22.57° ± 0.20°, 24.43° ± 0.20°, 26.32° ± 0.20°, 29.00° ± 0.20°, 29.40° ± 0.20°, 29.98° ± 0.20°, 31.23° ± 0.20°, 32.01° ± 0.20°, 32.75° ± 0.20°, 33.26° ± 0.20°, 34.60° ± 0.20°, 35.39° ± 0.20°, 36.55° ± 0.20°, 37.88° ± 0.20°, 38.44° ± 0.20°, 39.22° ± 0.20°.

[0035] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern, in terms of 2 theta, as shown in Figure 4.

[0036] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern obtained by the following parameters:

[0037] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has a differential scanning calorimetry curve (DSC) with one endothermic peak at 123.6±3.0°C (peak).

[0038] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has a differential scanning calorimetry curve (DSC) with a heat of fusion of the endothermic peak at 119.6-123.6°C of 81.65 J / g.

[0039] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has a differential scanning calorimetry curve as shown in Figure 5.

[0040] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has a thermogravimetric analysis curve (TGA) with a weight loss of 0.41% at 160.0°C.

[0041] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has a thermogravimetric analysis curve as shown in Figure 5.

[0042] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has a TGA and / or DSC pattern of the crystalline form obtained by the following parameters:

[0043] In some embodiments of the application, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt is an anhydrous crystalline form.

[0044] In some embodiments of the application, the molar ratio of the compound of formula (II) to the methanesulfonic acid is 1.0:1.

[0045] The application also provides a method for preparing the crystalline Form A of the compound of formula (II) methanesulfonic acid salt as described above, comprising the following steps:

[0046] mixing the compound of formula (II) and the methanesulfonic acid in an organic solvent, and separating after stirring;

[0047] Preferably, the organic solvent is butanone;

[0048] Preferably, the molar ratio of the methanesulfonic acid and the compound of formula (II) is 1.05:1.

[0049] The present application provides a crystalline Form A of the gentalinate salt of the compound of formula (II) having an X-ray powder diffraction pattern, expressed in 2Q, using Cu-Ka radiation, with diffraction peaks at the following positions: 8.54°±0.20°, 8.89°±0.20°, 12.70°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 19.45°±0.20°, 23.80°±0.20°;

[0050] In some embodiments of the present application, the crystalline Form A of the gentalinate salt of the compound of formula (II) has an X-ray powder diffraction pattern, expressed in 2Q, further having diffraction peaks at one or more of the following positions: 18.86°±0.20°, 22.31°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 27.78°±0.20°, 35.56°±0.20°.

[0051] In some embodiments of the present application, the crystalline Form A of the gentalinate salt of the compound of formula (II) has an X-ray powder diffraction pattern, expressed in 2Q, with diffraction peaks at the following positions: 8.54°±0.20°, 8.89°±0.20°, 12.70°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86°±0.20°, 19.45°±0.20°, 22.31°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 27.78°±0.20°, 35.56°±0.20°.

[0052] In some embodiments of the present application, the crystalline Form A of the gentalinate salt of the compound of formula (II) has an X-ray powder diffraction pattern, expressed in 2Q, further having diffraction peaks at one or more of the following positions: 11.66°±0.20°, 16.21°±0.20°, 22.71°±0.20°, 26.64°±0.20°, 36.12°±0.20°, 39.19°±0.20°.

[0053] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has an X-ray powder diffraction pattern, expressed in degrees 2-theta (2Q), with diffraction peaks at 8.54°±0.20°, 8.89°±0.20°, 11.66°±0.20°, 12.70°±0.20°, 16.21°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86°±0.20°, 19.45°±0.20°, 22.31°±0.20°, 22.71°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 26.64°±0.20°, 27.78°±0.20°, 35.56°±0.20°, 36.12°±0.20°, 39.19°±0.20°.

[0054] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has an X-ray powder diffraction pattern with the following peaks expressed in degrees 2-theta (2Q):

[0055] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has an X-ray powder diffraction pattern as shown in Figure 7.

[0056] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has an X-ray powder diffraction pattern obtained by the following parameters:

[0057] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has a differential scanning calorimetry curve (DSC) with an endothermic peak at 169.1±3.0°C (peak).

[0058] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has a differential scanning calorimetry curve (DSC) with a heat of fusion of the endothermic peak at 165.11-169.12°C of 115.1 J / g.

[0059] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has a differential scanning calorimetry curve as shown in Figure 8.

[0060] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has a thermogravimetric analysis curve (TGA) with a weight loss of 0.14% at 140.0°C.

[0061] In some embodiments of the application, the crystalline Form A of the compound gentisate of formula (II) has a thermogravimetric analysis curve as shown in Figure 8.

[0062] In some embodiments of the application, the crystalline Form A of the compound of formula (II) gentisate salt has a TGA and / or DSC pattern of the crystalline form obtained by the following parameters:

[0063] In some embodiments of the application, the crystalline Form A of the compound of formula (II) gentisate salt is an anhydrous crystalline form.

[0064] In some embodiments of the application, the molar ratio of the compound of formula (II) to the gentisic acid is 1.0:1.

[0065] The present application also provides a preparation method of the crystalline Form A of the compound of formula (II) gentisate salt as described above, which comprises the following steps:

[0066] Mixing the compound of formula (II) and gentisic acid in an organic solvent, and separating after stirring;

[0067] Preferably, the organic solvent is acetonitrile.

[0068] Preferably, the molar ratio of the gentisic acid to the compound of formula (II) is 1.05.

[0069] The present application provides a crystalline Form A of the compound of formula (II) tartarate salt, which has an X-ray powder diffraction pattern expressed in 2θ with Cu-Ka radiation having diffraction peaks at the following positions: 6.42°±0.20°, 13.08°±0.20°, 15.27°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 20.05°±0.20°;

[0070] In some embodiments of the application, the crystalline Form A of the compound of formula (II) tartarate salt has an X-ray powder diffraction pattern expressed in 2θ further having diffraction peaks at one or more of the following positions: 16.30°±0.20°, 19.74°±0.20°, 26.47°±0.20°.

[0071] In some embodiments of the application, the crystalline Form A of the compound of formula (II) tartarate salt has an X-ray powder diffraction pattern expressed in 2θ having diffraction peaks at the following positions: 6.42°±0.20°, 13.08°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 19.74°±0.20°, 20.05°±0.20°, 26.47°±0.20°.

[0072] In some embodiments of the application, the crystalline Form A of the tartaric acid salt of the compound of formula (II) further has an X-ray powder diffraction pattern, in terms of 2 theta, with diffraction peaks at one or more of the following positions: 12.03° ± 0.20°, 13.32° ± 0.20°, 23.17° ± 0.20°, 25.98° ± 0.20°.

[0073] In some embodiments of the application, the crystalline Form A of the tartaric acid salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2 theta, with diffraction peaks at the following positions: 6.42° ± 0.20°, 12.03° ± 0.20°, 13.08° ± 0.20°, 13.32° ± 0.20°, 15.27° ± 0.20°, 16.30° ± 0.20°, 17.59° ± 0.20°, 19.09° ± 0.20°, 19.74° ± 0.20°, 20.05° ± 0.20°, 23.17° ± 0.20°, 25.98° ± 0.20°, 26.47° ± 0.20°.

[0074] In some embodiments of the application, the crystalline Form A of the tartaric acid salt of the compound of formula (II) further has an X-ray powder diffraction pattern, in terms of 2 theta, with diffraction peaks at one or more of the following positions: 16.59° ± 0.20°, 21.02° ± 0.20°, 22.93° ± 0.20°, 28.47° ± 0.20°, 31.32° ± 0.20°, 32.13° ± 0.20°, 35.34° ± 0.20°.

[0075] In some embodiments of the application, the crystalline Form A of the tartaric acid salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2 theta, with diffraction peaks at the following positions: 6.42° ± 0.20°, 12.03° ± 0.20°, 13.08° ± 0.20°, 13.32° ± 0.20°, 15.27° ± 0.20°, 16.30° ± 0.20°, 16.59° ± 0.20°, 17.59° ± 0.20°, 19.09° ± 0.20°, 19.74° ± 0.20°, 20.05° ± 0.20°, 21.02° ± 0.20°, 22.93° ± 0.20°, 23.17° ± 0.20°, 25.98° ± 0.20°, 26.47° ± 0.20°, 28.47° ± 0.20°, 31.32° ± 0.20°, 32.13° ± 0.20°, 35.34° ± 0.20°.

[0076] In some embodiments of the application, the crystalline Form A of the tartrate salt of the compound of formula (II) further has an X-ray powder diffraction pattern, in terms of 2 theta (2 theta), with diffraction peaks at one or more of the following positions: 21.70° ± 0.20°, 27.04° ± 0.20°, 30.82° ± 0.20°, 35.78° ± 0.20°.

[0077] In some embodiments of the application, the crystalline Form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2 theta (2 theta), with diffraction peaks at the following positions: 6.42° ± 0.20°, 12.03° ± 0.20°, 13.08° ± 0.20°, 13.32° ± 0.20°, 15.27° ± 0.20°, 16.30° ± 0.20°, 16.59° ± 0.20°, 17.59° ± 0.20°, 19.09° ± 0.20°, 19.74° ± 0.20°, 20.05° ± 0.20°, 21.02° ± 0.20°, 21.70° ± 0.20°, 22.93° ± 0.20°, 23.17° ± 0.20°, 25.98° ± 0.20°, 26.47° ± 0.20°, 27.04° ± 0.20°, 28.47° ± 0.20°, 30.82° ± 0.20°, 31.32° ± 0.20°, 32.13° ± 0.20°, 35.34° ± 0.20°, 35.78° ± 0.20°.

[0078] In some embodiments of the application, the crystalline Form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2 theta (2 theta), with diffraction peaks at the following positions: 6.42° ± 0.20°, 12.03° ± 0.20°, 13.08° ± 0.20°, 13.32° ± 0.20°, 15.27° ± 0.20°, 16.30° ± 0.20°, 16.59° ± 0.20°, 17.59° ± 0.20°, 19.09° ± 0.20°, 19.74° ± 0.20°, 20.05° ± 0.20°, 21.02° ± 0.20°, 21.70° ± 0.20°, 22.93° ± 0.20°, 23.17° ± 0.20°, 25.98° ± 0.20°, 26.47° ± 0.20°, 27.04° ± 0.20°, 28.47° ± 0.20°, 30.82° ± 0.20°, 31.32° ± 0.20°, 32.13° ± 0.20°, 35.34° ± 0.20°, 35.78° ± 0.20°.

[0079] In some embodiments of the application, the crystalline Form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2 theta (2 theta), with diffraction peaks at the following positions: 6.42° ± 0.20°, 12.03° ± 0.20°, 13.08° ± 0.20°, 13.32° ± 0.20°, 15.27° ± 0.20°, 16.30° ± 0.20°, 16.59° ± 0.20°, 17.59° ± 0.20°, 19.09° ± 0.20°, 19.74° ± 0.20°, 20.05° ± 0.20°, 21.02° ± 0.20°, 21.70° ± 0.20°, 22.93° ± 0.20°, 23.17° ± 0.20°, 25.98° ± 0.20°, 26.47° ± 0.20°, 27.04° ± 0.20°, 28.47° ± 0.20°, 30.82° ± 0.20°, 31.32° ± 0.20°, 32.13° ± 0.20°, 35.34° ± 0.20°, 35.78° ± 0.20°.

[0080] In some embodiments of the application, the crystalline Form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2 theta (2 theta), with diffraction peaks at the following positions: 6.42° ± 0.20°, 12.03° ± 0.20°, 13.08° ± 0.20°, 13.32° ± 0.20°, 15.27° ± 0.20°, 16.30° ± 0.20°, 16.59° ± 0.20°, 17.59° ± 0.20°, 19.09° ± 0.20°, 19.74° ± 0.20°, 20.05° ± 0.20°, 21.02° ± 0.20°, 21.70° ± 0.20°, 22.93° ± 0.20°, 23.17° ± 0.20°, 25.98° ± 0.20°, 26.47° ± 0.20°, 27.04° ± 0.20°, 28.47° ± 0.20°, 30.82° ± 0.20°, 31.32° ± 0.20°, 32.13° ± 0.20°, 35.34° ± 0.20°, 35.78° ± 0.20°.

[0081] In some embodiments of the application, the crystalline Form A of the tartrate salt of the compound of formula (II) has a differential scanning calorimetry curve (DSC) with an endothermic peak at 132.7 ± 3.0 °C (peak).

[0082] In some embodiments of the application, the crystalline Form A of the tartrate salt of the compound of formula (II) has a differential scanning calorimetry curve (DSC) with a heat of fusion of the endothermic peak at 126.9 °C to 132.7 °C of 89.60 J / g.

[0083] In some embodiments of the present application, the crystalline form A of the tartaric acid salt of the compound of formula (II) has a differential scanning calorimetry curve as shown in Figure 11.

[0084] In some embodiments of the present application, the crystalline form A of the tartaric acid salt of the compound of formula (II) has a thermogravimetric analysis curve (TGA) with a weight loss of 0.34% at 130.0°C.

[0085] In some embodiments of the present application, the crystalline form A of the tartaric acid salt of the compound of formula (II) has a thermogravimetric analysis curve as shown in Figure 11.

[0086] In some embodiments of the present application, the crystalline form A of the tartaric acid salt of the compound of formula (II) has a TGA and / or DSC pattern of the crystalline form obtained by the following parameters:

[0087] In some embodiments of the present application, the crystalline form A of the tartaric acid salt of the compound of formula (II) is an anhydrous crystalline form.

[0088] In some embodiments of the present application, the molar ratio of the compound of formula (II) to the tartaric acid is 1.1:1.

[0089] The present application also provides a preparation method of the crystalline form A of the tartaric acid salt of the compound of formula (II) as described above, which comprises the following steps:

[0090] In an organic solvent, the compound of formula (II) and L-tartaric acid are mixed, and after stirring, the mixture is separated.

[0091] Preferably, the organic solvent is acetonitrile.

[0092] Preferably, the molar ratio of the L-tartaric acid to the compound of formula (II) is 1.05.

[0093] The present application also provides an application of a substance X in the preparation of a compound of formula (I), wherein the substance X is the crystalline form A of the tartaric acid salt of the compound of formula (II), the crystalline form A of the maleate salt of the compound of formula (II), the crystalline form A of the mesylate salt of the compound of formula (II), the crystalline form A of the gentisate salt of the compound of formula (II), or the crystalline form A of the tartaric acid salt of the compound of formula (II).

[0094] The compound of formula (I) is

[0095] Preferably, in the application, the substance X is prepared into the compound of formula (I) by the following route:

[0096] The present application provides a preparation method of a compound of formula (I), which comprises the following steps:

[0097] In some embodiments of the present application, the process for preparing the compound of formula (I) comprises the following steps:

[0098] In some embodiments of the present application, the process for preparing the compound of formula (I) comprises the following steps:

[0099] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined in any way, i.e. to obtain preferred embodiments of the present application.

[0100] The reagents and starting materials used in the present application are commercially available.

[0101] Definitions and explanations:

[0102] The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular phrase or term should not be construed as indefinite or unclear unless specifically defined, but should be construed in accordance with the ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0103] The intermediate compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by a combination of the specific embodiments listed below with other chemical synthetic methods well known to those skilled in the art, and equivalents thereof well known to those skilled in the art, preferred embodiments including but not limited to the embodiments of the present application. Those skilled in the art can appropriately change the starting materials, process conditions, etc. to achieve corresponding other purposes by referring to the content of the present application, and the related changes do not deviate from the content of the present application, and all similar replacements and modifications are obvious to those skilled in the art, and are considered to be included in the scope of the present application.

[0104] "Free form" refers to the free base form of the compound of formula (II).

[0105] "Crystal form" or "crystalline form" refers to a solid having a highly ordered chemical structure, including, but not limited to, single or multiple component crystals, and / or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of a compound. Crystalline forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, crystallization on a surface or template, e.g., on a polymer, crystallization in the presence of additives such as co-crystallizing counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent-drop grinding, etc.

[0106] A "solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present application include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, butanone, 1-methyl-2-pyrrolidinone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0107] A "antisolvent" refers to a fluid that promotes precipitation of a product (or a precursor to a product) from a solvent. An antisolvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that decreases the solubility of a product in a solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

[0108] A "solvate" refers to a crystal that has a solvent on the surface, or in the lattice, or both, wherein the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, butanone, methylpyrrolidinone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. One particular example of a solvate is a hydrate, wherein the solvent on the surface, or in the lattice, or both, is water. A hydrate can or can not have other solvents in addition to water on the surface, or in the lattice, or both.

[0109] Crystal forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solubility calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.

[0110] X-ray powder diffraction (XRPD) can detect information of polymorph, crystallinity, crystal structure, etc. and is a common method for identifying crystal polymorph. The peak position of XRPD pattern mainly depends on the structure of crystal polymorph and is relatively insensitive to experimental details, while the relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal polymorphs of the present application are characterized by XRPD patterns having certain peak positions, which are substantially as shown in the XRPD patterns provided in the drawings of the present application. Meanwhile, the measurement of 2Θ of XRPD pattern can have experimental error, and the measurement of 2Θ of XRPD pattern can be slightly different between different instruments and different samples, so the numerical value of 2Θ cannot be considered as absolute. According to the instrument used in the experiment of the present application, there is an error tolerance of ± 0.20° for the diffraction peak.

[0111] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al2O3) as a function of temperature under programmed heating or cooling. The melting peak height of DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal polymorphs of the present application are characterized by DSC patterns having characteristic peak positions, which are substantially as shown in the DSC patterns provided in the drawings of the present application. Meanwhile, the DSC pattern can have experimental error, and the peak position and peak value of the DSC pattern can be slightly different between different instruments and different samples, so the numerical value of the peak position or peak value of the DSC endothermic peak cannot be considered as absolute. According to the instrument used in the experiment of the present application, there is an error tolerance of ± 3°C for the melting peak.

[0112] Thermogravimetric analysis (TGA) is a technique that measures the mass of a substance as a function of temperature under programmed control, which is suitable for examining the process of solvent loss or sublimation, decomposition of the sample, and inferring the presence of crystalline water or crystalline solvent in the crystal. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA is slightly different between different instruments and different samples. According to the instrument used in the experiment of the present application, there is an error tolerance of ± 0.3% for the mass change.

[0113] In the preparation of pharmaceutical crystal polymorphs, it is difficult to avoid the situation that solvent molecules and compound molecules form co-crystals and remain in the solid substance during the contact process of solvent molecules and compound molecules caused by external conditions and internal factors, thereby forming solvates, including stoichiometric solvates and non-stoichiometric solvates. The solvates are included in the scope of the present application.

[0114] The chemical reactions of the present application are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical transformations being effected. For brevity, detailed discussions of reactions, protection schemes and the like are not provided. Skilled artisans will recognize that a number of synthetic routes can be adapted to prepare the compounds of the present application, and the following synthetic routes are not intended to be limiting.

[0115] All solvents used in the present application are commercially available.

[0116] The following abbreviations are used in the present application: Boc represents tert-butyloxycarbonyl; MEK represents methyl ethyl ketone; EtOAc, EA represent ethyl acetate; ACN represents acetonitrile; EtOH represents ethanol; n-Hep represents n-heptane; MTBE represents methyl tert-butyl ether; Toluene represents toluene.

[0117] Compounds are named according to conventional nomenclature methods in the art, and commercially available compounds are named according to the supplier's catalog name.

[0118] The positive progress effect of the present application is that:

[0119] 1) The maleate salt Form A, the mesylate salt Form A, the gentisate salt Form A or the tartrate salt Form A of the compound of formula (II) provided by the present application are all anhydrous crystal forms, have high crystallinity, good stability, can resist high temperature and high humidity, and have low hygroscopicity.

[0120] 2) The preparation method of the maleate salt Form A provided by the present application has high purity and yield of the product, mild and easy-to-control conditions, and good reproducibility.

[0121] 3) The preparation method of the compound of formula (I) provided by the present application has the advantages of commercial availability of reagents, low material cost, high utilization rate, high process yield, and safety, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0122] Figure 1 is the Cu-Ka radiation XRPD spectrum of the maleate salt Form A of the compound of formula (II);

[0123] Figure 2 is the DSC / TGA spectrum of the maleate salt Form A of the compound of formula (II);

[0124] Figure 3 is the Cu-Ka radiation XRPD spectrum of the mesylate salt Form A of the compound of formula (II); 1 Figure 3 is the Cu-Ka radiation XRPD spectrum of the mesylate salt Form A of the compound of formula (II);

[0125] Figure 4 is the Cu-Ka radiation XRPD spectrum of the mesylate salt Form A of the compound of formula (II);

[0126] Figure 5 is the DSC / TGA spectrum of the mesylate salt Form A of the compound of formula (II);

[0127] Figure 6 is the Cu-Ka radiation XRPD spectrum of the gentisate salt Form A of the compound of formula (II);1 H NMR spectrum;

[0128] Figure 7 is a Cu-Ka radiation XRPD pattern of the Gentioc acid salt Form A of the compound of formula (II);

[0129] Figure 8 is a DSC / TGA pattern of the Gentioc acid salt Form A of the compound of formula (II);

[0130] Figure 9 is a 1 H NMR spectrum;

[0131] Figure 10 is a Cu-Ka radiation XRPD pattern of the Tartaric acid salt Form A of the compound of formula (II);

[0132] Figure 11 is a DSC / TGA pattern of the Tartaric acid salt Form A of the compound of formula (II);

[0133] Figure 12 is a 1 H NMR spectrum;

[0134] Figure 13 is a comparison of XRPD patterns of the Maleic acid salt Form A of the compound of formula (II) after 2 days of storage under different conditions;

[0135] Figure 14 is a comparison of XRPD patterns of the Gentioc acid salt Form A of the compound of formula (II) after 2 days of storage under different conditions;

[0136] Figure 15 is a DVS pattern of the Maleic acid salt Form A of the compound of formula (II);

[0137] Figure 16 is a comparison of XRPD patterns of the Maleic acid salt Form A of the compound of formula (II) before and after DVS test. DETAILED DESCRIPTION

[0138] The application will be further described in the following examples, but the application is not limited to the examples described. The experimental methods in the following examples, where no specific conditions are indicated, were carried out according to conventional methods and conditions, or according to the instructions of the suppliers.

[0139] Instrument model:

[0140] Example 1 Synthesis of the compound of formula (II)

[0141] Synthesis route:

[0142] Step 1: Synthesis of intermediate 1-B

[0143] Intermediate 1-A (70 g) and 2,2,6,6-tetramethylpiperidine N-oxide (0.2 g) were dissolved in dichloromethane (700 mL), cooled to 0-5 °C, sodium bicarbonate (33.81 g), sodium bromide (2.65 g) were dissolved in water (420 mL), added to the reaction solution, sodium hypochlorite solution (372.12 g, 8% content), water (200 mL) were mixed uniformly, added dropwise to the reaction solution at 0-10 °C, stirred for 1 h, after the reaction was completed, sodium sulfite (100 g) was dissolved in water (1000 mL), added to the reaction solution to quench for 0.5 h, separated, dichloromethane (1 L) was added to extract again, the organic phase was combined, washed with brine (1 L) once, concentrated to obtain intermediate 1-B (68 g, yield: 98%). 1 H NMR (400 MHz, CDC13) δ ppm major [4.66 (s, 1H), 4.00 (s, 1H), 3.69 (s, 3H), 2.94 (s, 1H), 2.37-2.12 (m, 3H), 1.80 (s, 1H), 1.33 (s, 9H)]. minor [4.53 (s, 1H), 4.09 (s, 1H), 3.69 (s, 3H), 2.96 (s, 1H), 2.37-2.12 (m, 3H), 1.77 (s, 1H), 1.41 (s, 9H)]. MS m / z: 168.0 [M-Boc] +

[0144] Step 2: synthesis of intermediate 1-C

[0145] Methyltriphenylphosphonium bromide (103.47 g) was dissolved in toluene (650 mL), replaced with nitrogen for 3 times, cooled to 0-5 °C, added potassium tert-butoxide (29.79 g), warmed to 20-25 °C, stirred for 1 h, added intermediate 1-B (65 g), stirred at 20-25 °C for 16 h, after the reaction was completed, added water (1000 mL), extracted and separated, the aqueous phase was extracted again with methyl tert-butyl ether, the organic phase was combined, washed with brine (1000 mL), the organic phase was concentrated to dryness under reduced pressure, the concentrate was purified by column chromatography with petroleum ether-ethyl acetate to obtain intermediate 1-C (33 g, yield: 51%). 1H NMR (400 MHz, CDC13) δ ppm major [5.15 (d, J = 6.0 Hz, 1H), 4.85 (d, J = 6.0 Hz, 1H), 4.45 (s, 1H), 3.87 (s, 1H), 3.72 (s, 3H), 3.09 (s, 1H), 2.41 - 2.22 (m, 3H), 1.84 (s, 1H), 1.37 (s, 9H)]. minor [5.15 (d, J = 6.0 Hz, 1H), 4.85 (d, J = 6.0 Hz, 1H), 4.31 (s, 1H), 3.97 (s, 1H), 3.72 (s, 3H), 3.11 (s, 1H), 2.37 - 2.12 (m, 3H), 2.06 (s, 1H), 1.40 (s, 9H)]. MS m / z: 166.0 [M-Boc] +

[0146] Step 3: Synthesis of compound of formula (II)

[0147] Chlorobenzene (250 mL) was cooled to -10-0 °C, diethyl zinc n-hexane solution (1 mol / L, 561 mL) was added, after dropwise addition was completed, boron trifluoride ether (119.46 g) was added dropwise, and stirring was continued for 0.5 hours, cooled to -10 °C, diiodomethane (300.57 g) was added dropwise, and stirring was continued for 0.5 hours, intermediate 1-C (50 g) was dissolved in chlorobenzene (50 mL) and added dropwise to the reaction solution, after dropwise addition was completed, the temperature was raised to 35-40 °C and reacted for 4 hours, after the reaction was completed, the temperature was lowered to -10 to -5 °C, 20% aqueous citric acid solution (1000 mL) was added dropwise, after dropwise addition was completed, ethyl acetate (500 mL) was added, and stirring was continued for 10 minutes, the organic phase was washed with 20% aqueous citric acid solution (250 mL), the aqueous phase was combined, the aqueous phase was extracted with ethyl acetate (300 mL*2), the aqueous phase was added to an aqueous solution of potassium sodium tartrate [potassium sodium tartrate (316 g) + water (750 mL)], the pH was adjusted to 9-10 with ammonia water, dichloromethane (500 mL) was added, and the extraction was separated, the aqueous phase was re-extracted with dichloromethane (300 mL), and the organic phase was combined and concentrated under reduced pressure to obtain intermediate 1-D (24 g, yield: 70%). 1H NMR (400 MHz, CDC13) δ ppm 3.71 (s, 3H), 3.69 (s, 1H), 3.64 (d, J = 3.6 Hz, 1H), 1.86 (s, 1H), 1.72 - 1.67 (m, 2H), 1.52 - 1.47 (m, 2H), 0.70 - 0.59 (m, 3H), 0.40 - 0.38 (m, 1H). MS m / z: 182.1 [M+H] +

[0148] Synthesis of intermediate 1-A in Example 2

[0149] S1 (39 g, 141.6 mmol, 1 eq) was added into a 1000 mL round bottom flask under nitrogen protection, methanol 160 g, acetic acid (10.2 g, 170 mmol, 1.2 eq) was stirred and dissolved; 10% palladium-carbon 4.0 g was added, the hydrogen pressure was set to 0.3-0.5 MPa, the temperature was 10-20 °C, and the temperature was stirred for 8-10 hr; the TLC point plate showed that the raw material point disappeared; filtration; the filtrate was transferred to a 1000 mL round bottom flask, triethylamine was added dropwise at 5-5 °C, di-tert-butyl dicarbonate was added dropwise at 0-10 °C, the temperature was raised to 15-20 °C after dropping, and the temperature was stirred for 2-2.5 hr, and the TLC control showed that the raw material point disappeared; the reaction solution was concentrated under reduced pressure, ethyl acetate 180 g and drinking water 100 g were added, and the organic phase was separated by washing; the aqueous phase was extracted with ethyl acetate; the combined organic phase was washed with 12% sodium bicarbonate aqueous solution and 30% sodium chloride aqueous solution; the organic phase was dried with anhydrous sodium sulfate for 2 hr, filtered; concentrated under reduced pressure, and concentrated. 80.4 g of n-heptane was added at room temperature, and the slurry was stirred for 2-3 hr, filtered, and the filter cake was collected and dried under vacuum at 40-45 °C to obtain the target product intermediate 1-A (33.0 g, yield: 85.9%), 1 H NMR (400 MHz, DMSO-d6, 298 K, δ in ppm): 5.03 (m, 1H, CH), 3.94 (m, 1H, CH), 3.71 (s, 9H, C(CH3)3), 3.64 (d, 3H, CH3), 3.60 (d, 1H, CH), 3.34 (m, 2H, CH2), 2.41 (m, 1H, OH), 1.86 (m, 1H, CH), 1.63 (m, 2H, CH2).

[0150] Synthesis of intermediate 1 in Example 3

[0151] The compound of formula II was synthesized according to the method of Example 1 above.

[0152] Step 4: Synthesis of intermediate 1-E

[0153] The compound of formula II (137 g), (S)-N-Boc tert-leucine (192.32 g) was dissolved in a mixed solution of acetonitrile (1370 mL) and N,N-dimethylformamide (137 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (159.41 g), N-methylmorpholine (152.93 g), 1-hydroxybenzotriazole (102.14 g) were added at 25 °C, and the reaction was continued for 16 hours. After the reaction was completed, most of the acetonitrile was removed by concentration under reduced pressure, ethyl acetate (1000 mL), water (1000 mL) were added, and the mixture was extracted and separated. The organic phase was washed with 10% citric acid (500 mL*2), saturated sodium bicarbonate (500 mL), and saturated brine (500 mL), and concentrated to dryness under reduced pressure. The concentrate was added with hydrochloric acid ethyl acetate solution (4 mol / L, 1.89 L), and methanol (200 mL) at 10-15 °C, and stirred at 20-25 °C for 0.5 hours after the addition was completed. After the reaction was completed, 1 L of solvent was removed by concentration, and stirred at 25 °C for 0.5 hours. After filtration, the filter cake was washed with ethyl acetate (200 mL), and the residue was removed from the filter cake to obtain intermediate 1-E (212 g, yield: 85%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.49 (s, 3H), 4.51 (s, 1H), 4.42 (s, 1H), 4.03 (d, J = 4.8 Hz, 1H), 3.70 (s, 3H), 2.26 (d, J = 10.8 Hz, 1H), 2.07 (s, 1H), 1.97 (s, 1H), 1.90 (d, J = 10.0 Hz, 1H), 1.90 (d, J = 10.0 Hz, 1H), 1.80 (d, J = 12.4 Hz, 1H), 1.23 (s, 9H), 0.81-0.64 (m, 3H), 0.48-0.46 (m, 1H). MS m / z: 294.9 [M+H] +

[0154] Step 5: synthesis of intermediate 1

[0155] Intermediate 1-E (211.59 g) was dissolved in dichloromethane (1300 mL), trifluoroacetic anhydride (201.48 g) was added at 10-15 °C, triethylamine (64.71 g) was continuously added, after the addition was completed, the reaction was continued at 20-25 °C for 1 hour, after the reaction was completed, the reaction liquid was cooled to 10-15 °C, water (500 mL) was added dropwise, the liquid was separated, the organic phase was washed with 10% citric acid aqueous solution (500 mL), saturated sodium bicarbonate aqueous solution (500 mL), saturated brine (500 mL), concentrated to dryness to obtain the crude product of intermediate 1, isopropyl acetate (50 mL) and n-heptane (500 mL) were added to the crude product, and the slurry was prepared at 50 °C for 1-2 hours, cooled to 10-20 °C, filtered to obtain intermediate 1 (212 g, yield: 85%). 1 HNMR (400 MHz, CDC13) δ ppm 8.49 (d, J = 8.8 Hz, 1H), 4.68 (d, J = 9.6 Hz, 1H), 4.59 (s, 1H), 4.37 (s, 1H), 3.72 (s, 3H), 2.10 (d, J = 10.0 Hz, 1H), 1.99 (s, 1H), 1.92 - 1.86 (m, 2H), 1.59 (dd, J = 12.4 Hz, 2.4 Hz, 1H), 1.10 (s, 9H), 0.75 - 0.63 (m, 3H), 0.49 - 0.47 (m, 1H). MS m / z: 391.1 [M+H] + .

[0156] Example 4 Synthesis of compound of formula (I)

[0157] Step 6: Synthesis of intermediate 2

[0158] Intermediate 1 (640 g) was dissolved in MeOH (1280 ml) and THF (3840 ml), and an aqueous solution of LiOH.H2O (89.42 g of LiOH.H2O dissolved in 1280 ml of H2O) was added dropwise to the reaction system, which was controlled at a temperature of 30°C or less, and stirred for 16 hours. MTBE (5000 ml) and water (2500 ml) were added to the reaction solution, and stirred for 2 minutes, and the organic phase was washed with water (2500 ml). The water phases were combined, and the organic phase was back-extracted with water (5000 ml), and 1M HCl (3280 ml) was added to the water phase to adjust the pH to ~4, and EtOAc (5000 ml x 2) was added to extract the water phase, and the organic phases were combined, and the organic phase was washed with 1M HCl (2000 ml), saturated sodium chloride solution (2000 ml) in sequence, and the organic phase was dried over anhydrous sodium sulfate, and filtered under reduced pressure, and the filtrate was concentrated under reduced pressure at 50°C to obtain a yellow solid crude product. N-heptane (5V) was added to the crude product (calculated according to the mass of intermediate 1), and stirred for 10 minutes, and filtered under reduced pressure, and the filter cake was dried under reduced pressure at 50°C. Intermediate 2 (505 g, yield 81.9%) was obtained.

[0159] Step 7: Synthesis of intermediate 3

[0160] Intermediate 2 (315 g) was dissolved in 2-butanone (3150 ml) and DMF (315 ml), and HOBt (147.01 g) was added and stirred until clear, and BB-1 (208.56 g) was added, and the temperature was lowered to 0°C, and DIPEA (324.50 g) was slowly added, and the system was warmed to about 10°C, and when the temperature dropped to 0°C, EDCI (208.57 g) was added, and the temperature was naturally increased to 25°C, and stirred for 16 hours. Water (1000 ml) was added to the reaction system and stirred, and EtOAc (3000 ml) was added, and the liquid was separated, and the organic phase was washed with 5% citric acid (1500 ml x 2), and then washed with saturated sodium bicarbonate solution (1500 ml x 2), and washed with saturated sodium chloride solution (2000 ml), and all the water phases were extracted with EtOAc (1500 ml), and the organic phase was washed with 5% citric acid (750 ml), and then washed with saturated sodium bicarbonate solution (750 ml), and washed with saturated sodium chloride solution (1000 ml), and the combined organic phase was dried over anhydrous sodium sulfate, and filtered under reduced pressure, and the crude product was concentrated under reduced pressure at 50°C. MTBE (5V) was added and stirred for 1 hour, and filtered under reduced pressure, and the filter cake was dried under reduced pressure at 50°C to obtain intermediate 3 (312 g, yield 70.4%).

[0161] Step 8: Synthesis of the compound of formula (I)

[0162] Intermediate 3 (420 g) was dissolved in IPAc (4200 ml), NMM (497 g) was added, the temperature was lowered to 0-5 °C, TFAA (516 g) was added dropwise slowly, the temperature was slowly raised to 25 °C, and the mixture was stirred for 1 hr. The reaction was quenched by adding H2O (840 ml), and the mixture was stirred at 20-25 °C for 16 hrs. The reaction solution was washed with half-saturated sodium chloride solution (1400 ml x 2), 5% citric acid solution (1200 ml x 2), saturated sodium bicarbonate solution (1200 ml x 2), and deionized water (600 ml x 3). The aqueous phase was extracted with IPAc (1200 ml) and discarded. The IPAc phase was washed with 5% citric acid (400 ml), saturated sodium bicarbonate solution (400 ml), and deionized water (400 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 50 °C to give about 350 g of the compound of formula (I).

[0163] Example 5 Preparation of the compound of formula (II) in a preferred salt form

[0164] 1. Maleate salt Form A

[0165] Example 2 Preparation of the compound of formula (II) in a free form 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 6.03 (s, 2H), 4.18 (d, J = 25.5 Hz, 2H), 3.76 (s, 3H), 2.20 (d, J = 1.5 Hz, 1H), 1.95 (d, J = 11.2 Hz, 1H), 1.82 - 1.71 (m, 2H), 1.63 (dq, J = 11.2, 1.9 Hz, 1H), 0.84 (ddd, J = 9.9, 5.8, 4.0 Hz, 1H), 0.73 - 0.54 (m, 2H), 0.46 (ddd, J = 9.6, 6.1, 4.0 Hz, 1H) (XRPD, DSC, TGA and 1 The1H NMR spectra are shown in Figures 1, 2 and 3, respectively.

[0166] 2. Mesylate salt Form A

[0167] Example 1 was weighed out and stirred in ACN at room temperature overnight. The sample was centrifuged and dried at 30 °C under vacuum for 3-4 h to give 129.66 mg of a solid in 72.9% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 306.0 Hz, 2H), 4.19 (d, J = 26.3 Hz, 2H), 3.76 (s, 3H), 2.31 (s, 3H), 2.22 - 2.17 (m, 1H), 1.99 - 1.91 (m, 1H), 1.78 (d, J = 2.7 Hz, 2H), 1.63 (dd, J = 11.3, 2.0 Hz, 1H), 0.84 (ddd, J = 9.9, 5.9, 4.1 Hz, 1H), 0.69 - 0.54 (m, 2H), 0.46 (ddd, J = 9.6, 6.1, 4.1 Hz, 1H) (XRPD, DSC, TGA and 1 H NMR spectra are shown in Figures 4, 5 and 6 respectively.

[0168] 3. Gentisate salt Form A

[0169] Example 1 was weighed out and stirred in ACN at room temperature overnight. The sample was centrifuged and dried at 30 °C under vacuum for 3-4 h to give 129.66 mg of a solid in 72.9% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 306.0 Hz, 2H), 4.19 (d, J = 26.3 Hz, 2H), 3.76 (s, 3H), 2.31 (s, 3H), 2.22 - 2.17 (m, 1H), 1.99 - 1.91 (m, 1H), 1.78 (d, J = 2.7 Hz, 2H), 1.63 (dd, J = 11.3, 2.0 Hz, 1H), 0.84 (ddd, J = 9.9, 5.9, 4.1 Hz, 1H), 0.69 - 0.54 (m, 2H), 0.46 (ddd, J = 9.6, 6.1, 4.1 Hz, 1H) (XRPD, DSC, TGA and 1 H NMR spectra are shown in Figures 7, 8 and 9 respectively.

[0170] 4. L-tartrate salt Form A

[0171] Example 1. Weigh 102.03 mg of the free form of the compound of formula II prepared in Example 1 and 87.16 mg of L-tartaric acid (ligand / free form ratio of 1.05) in ACN system at room temperature with magnetic stirring overnight. After centrifugation, the sample was placed in a vacuum at 30 °C for 3-4 h to obtain 133.82 mg of solid, with a yield of 74.7%. 1 H NMR (400 MHz, DMSO-d6) δ 4.05 (d, J = 2.1 Hz, 2H), 3.92 (s, 1H), 3.83 (d, J = 3.1 Hz, 1H), 3.68 (d, J = 2.1 Hz, 3H), 2.00 (s, 1H), 1.77 (d, J = 10.3 Hz, 1H), 1.72 - 1.57 (m, 2H), 1.53 (dq, J = 10.4, 2.1 Hz, 1H), 0.75 (ddd, J = 9.7, 5.9, 3.9 Hz, 1H), 0.62 - 0.48 (m, 2H), 0.38 (ddd, J = 9.5, 6.1, 3.9 Hz, 1H) (XRPD, DSC, TGA and 1 H NMR spectra are shown in Figures 10, 11 and 12, respectively.

[0172] Table 1. Summary of preparation and characterization data of preferred salt forms

[0173] Example 6. Stability study of preferred salt forms of the compound of formula (II)

[0174] To further investigate the solid state properties of the preferred salt forms, the stability of the maleate salt Form A and the gentisate salt Form A were investigated at 25 °C / 60% RH and 40 °C / 75% RH, respectively. Specifically, ~10 mg of sample was weighed and placed at 25 °C / 60% RH and 40 °C / 75% RH, respectively, for two days. After two days, the samples were taken for XRPD and purity testing. The results are summarized in the following table. After two days at the two conditions, the maleate salt Form A and the gentisate salt Form A did not change. The XRPD results are shown in Figures 13 and 14.

[0175] Table 2. Summary of preliminary stability study of preferred salt forms (Figures 13-14)

[0176] Example 7. Hygroscopicity study data of the maleate salt Form A of the compound of formula (II)

[0177] The hygroscopicity of the maleate salt of the compound of formula (II) was evaluated at 25 °C using DVS, according to the following method:

[0178] 1) The sample was equilibrated at 0% RH for 30 min before starting the test;

[0179] 2) Relative humidity increase process: 0% RH to 90% RH at a rate of 10% RH per stage; 90% RH to 95% RH at a rate of 5% RH per stage;

[0180] 3) Relative humidity decrease process: 95% RH to 90% RH at a rate of 5% RH per stage; 90% RH to 0% RH at a rate of 10% RH per stage;

[0181] 4) After the DVS procedure is complete, sample for XRPD, store sample at 0% RH prior to testing.

[0182] DVS data showed that the first round of humidification process from 0% RH to 80% RH, the compound of formula (II) maleate salt had 0.1% weight gain, indicating no or little hygroscopicity; the sample at the end of DVS test was stored at 0% RH, and immediately tested for XRPD after taking out to room temperature and room humidity (16-20 °C, 25-60% RH), and the crystal form did not change, indicating good crystal form stability. DVS data is shown in Figures 15-16.

[0183] Example 1 Salt form screening of compound of formula (II)

[0184] A total of 52 salt form screening experiments were set up with various ligands in 4 solvent systems. Specifically, a stock solution of the starting free base of the compound of formula (II) was prepared (~20 mg per experiment), an equimolar amount of ligand was weighed into an HPLC vial, 0.2 mL of the free base stock solution was added, and magnetic stirring was performed at room temperature. After magnetic stirring at room temperature for ~1 day, 1) for the suspension sample, centrifugal separation was performed, and the sample was tested for XRPD; 2) for the clear or slightly turbid sample, it was transferred to 5 °C for cooling crystallization. If no obvious solid precipitated, it was transferred to -20 °C for standing. 3) for the gel sample, it was transferred to 50 °C for stirring and induction of crystal transformation. The obtained solid was centrifugally separated, and the sample was vacuum dried at 30 °C for ~3 h for characterization. The results are shown in Table 3:

[0185] Table 3 Salt form screening results of compound of formula (II)

[0186] Example 2 Solvent screening data for preferred salt form of compound of formula (II)

[0187] For 4 salt forms of the compound of formula (II), 6 solvent systems were selected for beating and salt screening. The specific experimental process was as follows: an equimolar amount of the starting sample and acid ligand was weighed into a 4 mL vial, the corresponding solvent was added, magnetic stirring was performed at 45 °C for 6 h, then the temperature was lowered to 10 °C for continued stirring for 6-7 h. For systems with more solids, the solids were separated, washed, and then the sample purity and XRPD were determined.

[0188] Table 4 Solvent screening data for 4 salts of the compound of formula (II)

Claims

1. A salt of a compound of formula (II) characterized in that, the salt is a maleate, mesylate, gentisate or tartrate salt; Preferably, the molar ratio of maleic acid, methanesulfonic acid, gentisic acid or tartaric acid to the compound of formula (II) is 1.1:1 or 1.0:1, more preferably 1.0:

1.

2. A crystalline Form A of the maleate salt of the compound of Formula (II), characterized by: which uses Cu-Ka radiation, has an X-ray powder diffraction pattern with diffraction peaks, given in degrees 2 theta, at 10.37°±0.20°, 13.75°±0.20°, 14.77°±0.20°, 19.47°±0.20°, 20.97°±0.20°, 21.67°±0.20°; 3. The crystalline Form A of the maleate salt of the compound of formula (II) according to claim 2, characterized in that, The X-ray powder diffraction pattern thereof further has diffraction peaks at one or more of the following positions: 11.67°±0.20°, 17.48°±0.20°, 19.75°±0.20°, 22.79°±0.20°, 23.48°±0.20°, 25.23°±0.20°, 26.93°±0.20°, 28.07°±0.20°, 29.80°±0.20°, 32.89°±0.20°, 38.37°±0.20°, in terms of 2θ.

4. The crystalline Form A of the maleate salt of the compound of formula (II) according to claim 2, characterized in that, The X-ray powder diffraction pattern thereof has diffraction peaks at the following positions: 10.37°±0.20°, 11.67°±0.20°, 13.75°±0.20°, 14.77°±0.20°, 17.48°±0.20°, 19.47°±0.20°, 19.75°±0.20°, 20.97°±0.20°, 21.67°±0.20°, 22.79°±0.20°, 23.48°±0.20°, 25.23°±0.20°, 26.93°±0.20°, 28.07°±0.20°, 29.80°±0.20°, 32.89°±0.20°, 38.37°±0.20°, in terms of 2θ. Preferably, the crystalline Form A of the compound of formula (II) maleate salt has an X-ray powder diffraction pattern, in terms of 2 theta, having the following peaks: More preferably, the crystal form A of the maleic acid salt of the compound of formula (II) has an X-ray powder diffraction pattern in terms of 2θ as shown in FIG.

1.

5. The crystalline Form A of the maleate salt of the compound of formula (II) according to claim 2, characterized in that, one or more of the following conditions are met: (1) the crystal form A of the maleic acid salt of the compound of formula (II) has a differential scanning calorimetry curve (DSC) with a heat of fusion of the endothermic peak at 135.6-143.8°C of 89.25 J / g; Preferably, the crystal form A of the maleic acid salt of the compound of formula (II) has a differential scanning calorimetry curve as shown in FIG. 2; (2) the crystal form A of the maleic acid salt of the compound of formula (II) has a thermogravimetric analysis curve (TGA) with a weight loss of 0.68% at 130.0°C; Preferably, the crystal form A of the maleic acid salt of the compound of formula (II) has a thermogravimetric analysis curve as shown in FIG. 2; (3) the crystal form A of the maleic acid salt of the compound of formula (II) is an anhydrous crystal form; (4) the molar ratio of the compound of formula (II) to the maleic acid is 1.0:

1.

6. The crystalline Form A of the maleate salt of the compound of formula (II) according to claim 5, characterized in that, one or more of the following conditions are met: (1) The crystalline Form A of the maleate salt of the compound of formula (II) is obtained by the X-ray powder diffraction pattern: (2) the crystalline Form A of the compound of formula (II) maleate salt is obtained by the following parameters for the TGA and / or DSC pattern of the crystalline form; 7. A process for preparing crystalline Form A of the maleate salt of the compound of formula (II) according to claim 2, characterized in that, It comprises the following steps: The compound of formula (II) and maleic acid are mixed in an organic solvent, and then separated after stirring. Preferably, the organic solvent is ethyl acetate. Preferably, the molar ratio of maleic acid to the compound of formula (II) is 1.05:

1.

8. A crystalline Form A of a compound of formula (II) methanesulfonate salt, characterized by, X-ray powder diffraction pattern, expressed in terms of 2 theta, having a diffraction peak at the following position: 7.23° ± 0.20°, 13.91° ± 0.20°, 16.36° ± 0.20°, 18.95° ± 0.20°, 19.71° ± 0.20°, 20.65° ± 0.20°, 21.94° ± 0.20°; using Cu-Ka radiation.

9. The crystalline Form A of the compound of formula (II) methanesulfonic acid salt according to claim 8, characterized in that, The X-ray powder diffraction pattern thereof further has diffraction peaks at one or more of the following positions: 9.92°±0.20°, 12.39°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 23.21°±0.20°, 24.03°±0.20°, in terms of 2θ. Preferably, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt further has an X-ray powder diffraction pattern, expressed in 2Θ, having also diffraction peaks at one or more of the following positions: 10.35°±0.20°, 11.83°±0.20°, 14.66°±0.20°, 21.36°±0.20°, 22.87°±0.20°, 24.92°±0.20°, 25.27°±0.20°, 26.60°±0.20°, 27.30°±0.20°, 28.34°±0.20°; More preferably, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt further has an X-ray powder diffraction pattern, expressed in 2Θ, having also diffraction peaks at one or more of the following positions: 8.23°±0.20°, 15.20°±0.20°, 22.57°±0.20°, 24.43°±0.20°, 26.32°±0.20°, 29.00°±0.20°, 29.40°±0.20°, 29.98°±0.20°, 31.23°±0.20°, 32.01°±0.20°, 32.75°±0.20°, 33.26°±0.20°, 34.60°±0.20°, 35.39°±0.20°, 36.55°±0.20°, 37.88°±0.20°, 38.44°±0.20°, 39.22°±0.20°.

10. The crystalline Form A of the compound of formula (II) methanesulfonic acid salt according to claim 8, characterized in that, having also diffraction peaks at one or more of the following positions: 7.23°±0.20°, 9.92°±0.20°, 13.91°±0.20°, 16.36°±0.20°, 12.39°±0.20°, 17.85°±0.20°, 18.59°±0.20°, 18.95°±0.20°, 19.71°±0.20°, 20.65°±0.20°, 21.94°±0.20°, 23.21°±0.20°, 24.03°±0.20°; Preferably, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern, expressed in 2Q, having diffraction peaks at the following positions: 7.23° ± 0.20°, 9.92° ± 0.20°, 10.35° ± 0.20°, 11.83° ± 0.20°, 12.39° ± 0.20°, 13.91° ± 0.20°, 14.66° ± 0.20°, 16.36° ± 0.20°, 17.85° ± 0.20°, 18.59° ± 0.20°, 18.95° ± 0.20°, 19.71° ± 0.20°, 20.65° ± 0.20°, 21.36° ± 0.20°, 21.94° ± 0.20°, 22.87° ± 0.20°, 23.21° ± 0.20°, 24.03° ± 0.20°, 24.92° ± 0.20°, 25.27° ± 0.20°, 26.60° ± 0.20°, 27.30° ± 0.20°, 28.34° ± 0.20°; More preferably, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern, expressed in 2Q, having diffraction peaks at the following positions: 7.23° ± 0.20°, 8.23° ± 0.20°, 9.92° ± 0.20°, 10.35° ± 0.20°, 11.83° ± 0.20°, 12.39° ± 0.20°, 13.91° ± 0.20°, 14.66° ± 0.20°, 15.20° ± 0.20°, 16.36° ± 0.20°, 17.85° ± 0.20°, 18.59° ± 0.20°, 18.95° ± 0.20°, 19.71° ± 0.20°, 20.65° ± 0.20°, 21.36° ± 0.20°, 21.94° ± 0.20°, 22.57° ± 0.20°, 22.87° ± 0.20°, 23.21° ± 0.20°, 24.03° ± 0.20°, 24.43° ± 0.20°, 24.92° ± 0.20°, 25.27° ± 0.20°, 26.32° ± 0.20°, 26.60° ± 0.20°, 27.30° ± 0.20°, 28.34° ± 0.20°, 29.00° ± 0.20°, 29.40° ± 0.20°, 29.98° ± 0.20°, 31.23° ± 0.20°, 32.01° ± 0.20°, 32.75° ± 0.20°, 33.26° ± 0.20°, 34.60° ± 0.20°, 35.39° ± 0.20°, 36.55° ± 0.20°, 37.88° ± 0.20°, 38.44° ± 0.20°, 39.22° ± 0.20°; More preferably, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern, in terms of 2Θ, having diffraction peaks as shown in the following table: Most preferably, the crystalline Form A of the compound of formula (II) methanesulfonic acid salt has an X-ray powder diffraction pattern, expressed in 2Q, as shown in Figure 4.

11. The crystalline Form A of the compound of formula (II) methanesulfonic acid salt according to claim 8, characterized in that, one or more of the following conditions: (1) the crystalline form A of the compound of formula (II) methanesulfonic acid salt, the differential scanning calorimetry curve (DSC) thereof has a heat of fusion of 81.65 J / g at the endothermic peak at 119.6-123.6 °C; Preferably, the crystalline form A of the compound of formula (II) methanesulfonic acid salt, the differential scanning calorimetry curve thereof is as shown in Figure 5; (2) the crystalline form A of the compound of formula (II) methanesulfonic acid salt, the thermogravimetric analysis curve (TGA) thereof has a weight loss of 0.41% at 160.0 °C; Preferably, the crystalline form A of the compound of formula (II) methanesulfonic acid salt, the thermogravimetric analysis curve thereof is as shown in Figure 5; (3) the crystalline form A of the compound of formula (II) methanesulfonic acid salt is an anhydrous crystalline form; (4) the molar ratio of the compound of formula (II) to the methanesulfonic acid is 1.0:

1.

12. A process for preparing crystalline Form A of the mesylate salt of the compound of formula (II) as claimed in claim 8, characterized in that, It comprises the following steps: mixing the compound of formula (II) and the methanesulfonic acid in an organic solvent, and separating after stirring; Preferably, the organic solvent is butanone; Preferably, the molar ratio of the methanesulfonic acid to the compound of formula (II) is 1.05:

1.

13. A crystalline Form A of a gondic acid salt of a compound of Formula (II), characterized by: X-ray powder diffraction pattern, expressed in terms of 2 theta, having a diffraction peak at the following position: 8.54° ± 0.20°, 8.89° ± 0.20°, 12.70° ± 0.20°, 17.42° ± 0.20°, 18.04° ± 0.20°, 19.45° ± 0.20°, 23.80° ± 0.20°; 14. The crystalline Form A of the gntic acid salt of the compound of formula (II) according to claim 13, characterized in that, The X-ray powder diffraction pattern thereof further has diffraction peaks at one or more of the following positions: 8.54°±0.20°, 8.89°±0.20°, 12.70°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86°±0.20°, 19.45°±0.20°, 22.31°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 27.78°±0.20°, 35.56°±0.20°, expressed in terms of 2θ; Preferably, the X-ray powder diffraction pattern of the crystalline form A of the compound of formula (II) gentisate salt, expressed in terms of 2θ, further has diffraction peaks at one or more of the following positions: 11.66°±0.20°, 16.21°±0.20°, 22.71°±0.20°, 26.64°±0.20°, 36.12°±0.20°, 39.19°±0.20°.

15. The crystalline Form A of the gntic acid salt of the compound of formula (II) according to claim 13, characterized in that, The X-ray powder diffraction pattern thereof further has diffraction peaks at one or more of the following positions: 8.54°±0.20°, 8.89°±0.20°, 12.70°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86°±0.20°, 19.45°±0.20°, 22.31°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 27.78°±0.20°, 35.56°±0.20°, expressed in terms of 2θ; Preferably, the crystalline Form A of the compound of formula (II) gentisate salt has an X-ray powder diffraction pattern expressed in terms of 2Q with diffraction peaks at 8.54°±0.20°, 8.89°±0.20°, 11.66°±0.20°, 12.70°±0.20°, 16.21°±0.20°, 17.42°±0.20°, 18.04°±0.20°, 18.86°±0.20°, 19.45°±0.20°, 22.31°±0.20°, 22.71°±0.20°, 23.80°±0.20°, 25.40°±0.20°, 25.77°±0.20°, 26.64°±0.20°, 27.78°±0.20°, 35.56°±0.20°, 36.12°±0.20°, 39.19°±0.20°; More preferably, the crystalline Form A of the gentisate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2 theta, having the following peaks: More preferably, the crystalline Form A of the compound of formula (II) gentisate salt has an X-ray powder diffraction pattern as shown in Figure 7.

16. The crystalline Form A of the gntic acid salt of the compound of formula (II) according to claim 13, characterized in that, one or more of the following conditions: (1) the crystalline Form A of the compound of formula (II) gentisate salt has a differential scanning calorimetry curve (DSC) with a heat of fusion of the endothermic peak at 165.11-169.12°C of 115.1 J / g; Preferably, the crystalline Form A of the compound of formula (II) gentisate salt has a differential scanning calorimetry curve as shown in Figure 8; (2) the crystalline Form A of the compound of formula (II) gentisate salt has a thermogravimetric analysis curve (TGA) with a weight loss of 0.14% at 140.0°C; Preferably, the crystalline Form A of the compound of formula (II) gentisate salt has a thermogravimetric analysis curve as shown in Figure 8; (3) the crystalline Form A of the compound of formula (II) gentisate salt is an anhydrous crystalline form; (4) the molar ratio of the compound of formula (II) to the gentisate is 1.0:

1.

17. The crystalline Form A of the gntic acid salt of the compound of formula (II) according to claim 16, characterized in that, one or more of the following conditions: (1) the crystalline Form A of the gentisate salt of the compound of formula (II) is obtained by the X-ray powder diffraction pattern of the following parameters; (2) the crystalline Form A of the compound gentisate salt of formula (II) is obtained by the following parameters for the TGA and / or DSC pattern of the crystalline form; 18. A process for preparing a crystalline Form A of a gondic acid salt of a compound of formula (II) as claimed in claim 13, characterized in that, which comprises the following steps: mixing the compound of formula (II) and gentisate in an organic solvent, and separating after stirring; Preferably, the organic solvent is acetonitrile; Preferably, the molar ratio of the gentisate to the compound of formula (II) is 1.

05.

19. A crystalline Form A of a tartrate salt of a compound of Formula (II) characterized by: X-ray powder diffraction pattern, expressed in terms of 2 theta, having a diffraction peak at the following position: 6.42° ± 0.20°, 13.08° ± 0.20°, 15.27° ± 0.20°, 17.59° ± 0.20°, 19.09° ± 0.20°, 20.05° ± 0.20°; using Cu-Ka radiation; 20. The crystalline Form A of the tartrate salt of the compound of formula (II) according to claim 19, characterized in that, the X-ray powder diffraction pattern expressed in terms of 2Q further has diffraction peaks at one or more of the following positions: 16.30°±0.20°, 19.74°±0.20°, 26.47°±0.20°; Preferably, the crystalline Form A of the compound of formula (II) tartrate salt has an X-ray powder diffraction pattern expressed in terms of 2Q further with diffraction peaks at one or more of the following positions: 12.03°±0.20°, 13.32°±0.20°, 23.17°±0.20°, 25.98°±0.20°; More preferably, the crystalline Form A of the compound of formula (II) tartrate salt further has an X-ray powder diffraction pattern, expressed in angles 2Q, with diffraction peaks at one or more of the following positions: 21.70°±0.20°, 27.04°±0.20°, 30.82°±0.20°, 35.78°±0.20°. More preferably, the crystalline Form A of the compound of formula (II) tartrate salt further has an X-ray powder diffraction pattern, expressed in angles 2Q, with diffraction peaks at one or more of the following positions: 21.70°±0.20°, 27.04°±0.20°, 30.82°±0.20°, 35.78°±0.20°.

21. The crystalline Form A of the tartrate salt of the compound of formula (II) according to claim 19, characterized in that, More preferably, the crystalline Form A of the compound of formula (II) tartrate salt further has an X-ray powder diffraction pattern, expressed in angles 2Q, with diffraction peaks at one or more of the following positions: 21.70°±0.20°, 27.04°±0.20°, 30.82°±0.20°, 35.78°±0.20°. More preferably, the crystalline Form A of the compound of formula (II) tartrate salt further has an X-ray powder diffraction pattern, expressed in angles 2Q, with diffraction peaks at one or more of the following positions: 21.70°±0.20°, 27.04°±0.20°, 30.82°±0.20°, 35.78°±0.20°. More preferably, the crystalline Form A of the compound of formula (II) tartrate salt further has an X-ray powder diffraction pattern, expressed in angles 2Q, with diffraction peaks at one or more of the following positions: 21.70°±0.20°, 27.04°±0.20°, 30.82°±0.20°, 35.78°±0.20°. More preferably, the crystalline form A of the tartaric acid salt of the compound of formula (II) has an X-ray powder diffraction pattern, expressed in 2q, having diffraction peaks at the following positions: 6.42°±0.20°, 12.03°±0.20°, 13.08°±0.20°, 13.32°±0.20°, 15.27°±0.20°, 16.30°±0.20°, 16.59°±0.20°, 17.59°±0.20°, 19.09°±0.20°, 19.74°±0.20°, 20.05°±0.20°, 21.02°±0.20°, 21.70°±0.20°, 22.93°±0.20°, 23.17°±0.20°, 25.98°±0.20°, 26.47°±0.20°, 27.04°±0.20°, 28.47°±0.20°, 30.82°±0.20°, 31.32°±0.20°, 32.13°±0.20°, 35.34°±0.20°, 35.78°±0.20°; More preferably, the crystalline Form A of the tartrate salt of the compound of formula (II) has an X-ray powder diffraction pattern, in terms of 2Θ, having diffraction peaks as shown in the following table: Most preferably, the crystalline form A of the tartaric acid salt of the compound of formula (II) has an X-ray powder diffraction pattern as shown in Figure 10.

22. The crystalline Form A of the gntic acid salt of the compound of formula (II) according to claim 19, characterized in that, one or more of the following conditions: (1) the crystalline form A of the tartaric acid salt of the compound of formula (II) has a differential scanning calorimetry curve with a heat of fusion of the endothermic peak at 126.9-132.7 °C of 89.60 J / g; Preferably, the crystalline form A of the tartaric acid salt of the compound of formula (II) has a differential scanning calorimetry curve as shown in Figure 11; (2) the crystalline form A of the tartaric acid salt of the compound of formula (II) has a thermogravimetric analysis curve (TGA) with a weight loss of 0.34% at 130.0 °C; Preferably, the crystalline form A of the tartaric acid salt of the compound of formula (II) has a thermogravimetric analysis curve as shown in Figure 11; (3) the crystalline form A of the tartaric acid salt of the compound of formula (II) is an anhydrous crystalline form; (4) the molar ratio of the compound of formula (II) to the tartaric acid is 1.1:

1.

23. A process for preparing crystalline Form A of a tartrate salt of a compound of formula (II) as claimed in claim 19, characterized in that, which comprises the following steps: mixing the compound of formula (II) and L-tartaric acid in an organic solvent, and separating after stirring; Preferably, the organic solvent is acetonitrile; Preferably, the molar ratio of the L-tartaric acid to the compound of formula (II) is 1.

05.

24. Use of a substance X for the preparation of a compound of formula (I), characterized in that said substance X is the compound of formula (II) according to claim 1, a salt of the compound of formula (II), the crystalline form A of the maleic acid salt according to any one of claims 2 to 6, the crystalline form A of the methanesulfonic acid salt according to any one of claims 8 to 11, the crystalline form A of the gentisic acid salt according to any one of claims 13 to 17, or the crystalline form A of the tartaric acid salt according to any one of claims 19 to 22; The compound of formula (I) is Preferably, in said use, said substance X is prepared by the following route to give the compound of formula (I):

25. A process for the preparation of a compound of formula (I) ###00010### (I) characterized in that, It comprises the steps of:

26. The production method according to claim 25, wherein It comprises the following steps:

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