Ad-35 polymorphs, preparation methods therefor, and use thereof

Abstract

The present invention provides crystalline forms of 6-[2-[1-(2-pyridylmethyl)-4-piperidyl]ethyl]spiro[[1,3]dioxolo[4,5-f]isoindole-7,1'-cyclopropane]-5-one phosphate (AD-35), and preparation methods therefor. The invention further provides a use of the crystalline forms of AD-35 in the preparation of a drug for treating Alzheimer's disease.

Description

AD-35 polymorphs and their preparation and use Technical Field

[0001] The present invention relates to a polymorph of AD-35 and a preparation method thereof, specifically a polymorph of 6-[2-[1-(2-pyridylmethyl)-4-piperidinyl]ethyl]spiro[[1,3]dioxolo[4,5-f]isoindole-7,1'-cyclopropane]-5-one phosphate (AD-35) and a corresponding preparation method thereof. Background Art

[0002] WO2014005421 reports a new class of benzodioxole compounds that inhibit acetylcholinesterase and are potentially useful in treating Alzheimer's disease. Particularly noteworthy among these compounds is compound AD-35, whose chemical name is 6-[2-[1-(2-pyridylmethyl)-4-piperidinyl]ethyl]spiro[[1,3]dioxolo[4,5-f]isoindole-7,1'-cyclopropane]-5-one phosphate, and whose chemical structure is as follows:

[0003] Why is AD-35 so eye-catching? Because compared with donepezil, it is a relatively weak acetylcholinesterase inhibitor. Its in vitro acetylcholinesterase inhibitory activity is about one-tenth of donepezil's activity. However, this compound showed comparable efficacy to donepezil in the Morris water maze test, that is, its effect on improving memory and learning ability was comparable to donepezil. Further studies have found that in addition to inhibiting acetylcholinesterase activity, AD-35 can also significantly inhibit the production of Aβ. 25-35 Induced production and release of pro-inflammatory cytokines TNF-α and IL-1β, thereby significantly reducing Aβ 25-35 In vitro experiments also found that AD-35 has a certain chelating effect on transition metal ions such as Cu 2+ ability and can inhibit the Cu 2+ Induced Aβ aggregation and disaggregation in Cu 2+ Thus, AD-35 is a multi-mechanism, multifunctional compound (Li et al. Journal of Alzheimer's Disease 2017, 56(4), 1403), which protects nerve cells through multiple mechanisms.

[0004] AD-35's safety profile is also highly impressive. A completed Phase I single ascending dose (SAD) trial demonstrated no adverse reactions in subjects taking a single 90 mg dose of AD-35. A multiple ascending dose (MAD) trial further demonstrated no adverse reactions in subjects taking 120 mg of AD-35 once daily for two weeks.

[0005] In summary, AD-35 has great potential to become a new drug for treating Alzheimer's disease with minimal side effects. Its multiple mechanisms of action are likely to enable this compound to not only alleviate the symptoms of Alzheimer's patients, but also delay the progression of the disease.

[0006] For drugs, different crystal forms lead to different physical and chemical properties of polymorphic drugs, such as melting point, apparent solubility, dissolution rate, optical and mechanical properties, crystallinity, crystal habit, particle size and size distribution, particle aggregation state, density, filtration and grinding, crushing, powdering, etc., which in turn affect the characteristics of the dosage form, such as flowability, dissolution, bioavailability and stability. These physical and chemical properties directly determine whether a specific crystal form is the dominant crystal form and whether it can be made into a drug, and directly affect the quality of the raw materials and preparations. Therefore, it is necessary to study the crystal form of AD-35 and the properties of each crystal form to meet the practical application of AD-35. Summary of the Invention

[0007] The present invention relates to stable polymorphs of 6-[2-[1-(2-pyridylmethyl)-4-piperidinyl]ethyl]spiro[[1,3]dioxolo[4,5-f]isoindole-7,1'-cyclopropane]-5-one phosphate (AD-35), which are respectively crystal form (I), crystal form (II), crystal form (III), crystal form (IV), crystal form (V), crystal form (VI), and amorphous form (VII). A preparation method of the AD-35 polymorphs is also provided.

[0008] In one aspect of the present invention, a crystalline form (I) of AD-35 is provided, whose X-ray powder diffraction (XRPD) pattern has characteristic peaks at the following diffraction angles 2θ: 7.2±0.2°, 7.8±0.2°, 14.2±0.2°, 16.1±0.2°, 16.5±0.2°, 21.0±0.2°, and 23.5±0.2°.

[0009] Furthermore, the X-ray powder diffraction pattern of the AD-35 crystal form (I) has characteristic peaks at the following diffraction angles 2θ: 12.8±0.2°, 16.7±0.2°, 17.6±0.2°, 18.7±0.2°, 19.3±0.2°, 20.0±0.2°, 21.7±0.2°, 24.1±0.2°, 26.6±0.2°. Furthermore, preferably, the X-ray powder diffraction spectrum of the AD-35 crystal form (I) of the present invention has the 2θ, d value and relative intensity data shown in Table 1 below:

[0010] Table 1

[0011] Without limitation, the crystalline form (I) of AD-35 of the present invention has an X-ray powder diffraction spectrum as shown in FIG1 .

[0012] In addition, the infrared absorption spectrum of the crystal form (I) of AD-35 of the present invention in potassium bromide is about 454.4 cm -1 , 504.8cm -1 , 535.8cm -1 , 568.1cm -1 , 757.3cm -1 , 779.5cm -1 , 861.4cm -1 , 874.8cm -1 , 925.6cm -1 , 951.0cm -1 , 1027.9cm -1 , 1073.2cm -1 , 1127.9cm -1 , 1165.3cm -1 , 1247.6cm -1 , 1282.0cm -1 , 1368.2cm -1 , 1411.0cm -1 , 1475.2cm -1 , 1590.1cm -1 , 1620.7cm -1 , 1671.9cm -1 , 2859.6cm -1 , 2918.1cm -1 , 3047.8cm -1 , 3440.8cm -1 There is an absorption peak at.

[0013] Without limitation, the crystalline form (I) of AD-35 of the present invention has an infrared spectrum as shown in FIG8 .

[0014] The differential scanning calorimetry (DSC) spectrum of the crystalline form (I) of AD-35 described in the present invention has a maximum endothermic peak at 223±5°C.

[0015] Without limitation, the crystalline form (I) of AD-35 of the present invention has a DSC spectrum as shown in FIG15 .

[0016] Without limitation, the crystalline form (I) of AD-35 of the present invention has a TGA spectrum as shown in FIG22 .

[0017] Another object of the present invention is to provide a method for preparing AD-35 crystal form (I), which is selected from any one of the following methods:

[0018] The compound of formula A with the following structure is the free base of AD-35, namely 6-[2-[1-(2-pyridylmethyl)-4-piperidinyl]ethyl]spiro[[1,3]dioxolo[4,5-f]isoindole-7,1'-cyclopropane]-5-one.

[0019] Method (1), comprising the following steps:

[0020] 1) dissolving the compound represented by formula A in an organic solvent a; the dissolution temperature is 30-130° C., preferably 40-90° C.; the organic solvent a is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, toluene, ethanol, ethyl acetate, N,N-dimethylformamide, methanol, chloroform, and acetone; the volume-to-mass ratio (ml / g) of the organic solvent a to the compound represented by formula A is 8-100:1, preferably 10-50:1;

[0021] 2) adding dropwise an organic solvent b containing phosphoric acid; the molar ratio of the phosphoric acid to the compound of formula A is 0.95 to 1.05:1, and the organic solvent b is selected from one or more of ethanol, tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, and acetone; the volume-to-mass ratio (ml / g) of the organic solvent b to the compound of formula A is 2 to 20:1;

[0022] 3) stirring and crystallizing; the stirring rate is 60 to 1500 rpm, preferably 120 to 1000 rpm; the crystallization temperature is -25 to 30°C;

[0023] 4) Filter to obtain the crystalline form (I) of AD-35.

[0024] Method (2), comprising the following steps:

[0025] 1) adding AD-35 to a mixed solvent of an organic solvent and water, heating under reflux to dissolve; the mass volume ratio (g / ml) of AD-35 to the mixed solvent is 1:10.4-66; the volume ratio of the organic solvent to water is 5-30:1; the organic solvent is selected from one or more of ethanol, isopropanol, tetrahydrofuran, acetone, n-pentanol, ethyl acetate, n-butanol, N,N-dimethylformamide, dichloromethane, acetonitrile, and dimethyl sulfoxide;

[0026] 2) standing or stirring at -25 to 30°C for crystallization; or, adding an organic solvent dropwise at -25 to 30°C for crystallization; the organic solvent is selected from one or more of methyl tert-butyl ether, isopropyl alcohol, tetrahydrofuran, and ethyl acetate; the volume ratio (ml / g) of the organic solvent to the mixed solvent in step (1) is 0.5 to 6:1;

[0027] 3) Filter to obtain the crystalline form (I) of AD-35.

[0028] Method (3), comprising the following steps:

[0029] AD-35 crystalline form (IV), AD-35 crystalline form (V), or AD-35 amorphous form (VII) is stirred in ethanol at 40-80°C for 4-48 hours, cooled to room temperature, and filtered to obtain AD-35 crystalline form (I); the mass volume ratio (g / ml) of the AD-35 to ethanol is 1:20-50.

[0030] Method (4), comprising the following steps:

[0031] AD-35 crystal form (IV) or AD-35 crystal form (V) is heated at high temperature for 3h to 7h to obtain AD-35 crystal form (I), wherein the high temperature heating temperature is 120°C to 200°C.

[0032] Another aspect of the present invention provides a crystalline form (II) of AD-35, whose X-ray powder diffraction (XRPD) pattern has characteristic peaks at the following diffraction angles 2θ: 6.8±0.2°, 12.7±0.2°, 16.6±0.2°, 20.2±0.2°, 20.8±0.2°, and 22.6±0.2°.

[0033] Furthermore, the X-ray powder diffraction pattern of the AD-35 crystal form (II) has characteristic peaks at the following diffraction angles 2θ: 13.8±0.2°, 19.6±0.2°, 20.0±0.2°, 24.7±0.2°, 28.0±0.2°. Furthermore, preferably, the X-ray powder diffraction spectrum of the AD-35 crystal form (II) of the present invention has the 2θ, d and relative intensity data shown in Table 2 below:

[0034] Table 2

[0035] Without limitation, the crystalline form (II) of AD-35 of the present invention has an X-ray powder diffraction spectrum as shown in FIG2 .

[0036] In addition, the infrared absorption spectrum of the crystal form (II) of AD-35 described in the present invention in potassium bromide is about 529.1 cm -1 , 762.6cm -1 , 777.1cm -1 , 866.4cm -1 , 934.5cm -1 , 955.6cm -1 , 1029.3cm -1 , 1128.2cm -1 , 1163.9cm -1 , 1245.9cm -1 , 1288.1cm -1 , 1352.0cm -1 , 1369.9cm -1 , 1413.2cm - 1 , 1474.2cm -1 , 1600.4cm -1 , 1618.1cm -1 , 1677.7cm -1 , 2841.1cm -1 , 2923.9cm -1 , 3424.7cm -1 There is an absorption peak at.

[0037] Without limitation, the crystalline form (II) of AD-35 of the present invention has an infrared spectrum as shown in FIG9 .

[0038] The differential scanning calorimetry (DSC) spectrum of the crystal form (II) of AD-35 described in the present invention has a maximum endothermic peak at 224±5°C.

[0039] Without limitation, the crystalline form (II) of AD-35 of the present invention has a DSC spectrum as shown in FIG16 .

[0040] Without limitation, the crystalline form (II) of AD-35 of the present invention has a TGA spectrum as shown in FIG23 .

[0041] Another object of the present invention is to provide a method for preparing AD-35 crystal form (II), which comprises:

[0042] (1) dissolving the compound represented by formula A in an alcohol solvent; the dissolution temperature is 50-70° C.; the mass volume ratio (g / ml) of the compound A to the alcohol solvent is 1:4-6; the alcohol solvent is a C2-C4 alcohol, preferably ethanol and isopropanol;

[0043] (2) adding phosphoric acid while stirring; the molar ratio of the phosphoric acid to the compound of formula A is 0.4 to 0.85:1; the stirring rate is 10 to 180 rpm;

[0044] (3) adding ethyl acetate dropwise; the volume ratio (ml / g) of the alcohol solvent to ethyl acetate in step (1) is 1:1-2;

[0045] (4) Filtration to obtain the crystal form (II) of AD-35.

[0046] Another aspect of the present invention provides a crystalline form (III) of AD-35, whose X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 9.2±0.2°, 18.2±0.2°, 18.5±0.2°, 20.4±0.2°, and 23.9±0.2°.

[0047] Furthermore, the X-ray powder diffraction pattern of the AD-35 crystal form (III) has characteristic peaks at the following diffraction angles 2θ: 11.5±0.2°, 15.4±0.2°, 19.0±0.2°, 22.1±0.2°, 25.9±0.2°, and 26.8±0.2°.

[0048] Furthermore, preferably, the X-ray powder diffraction spectrum of the crystalline form (III) of AD-35 of the present invention has the 2θ, d and relative intensity data shown in Table 3 below:

[0049] Table 3 XRPD data of form (III) of AD-35

[0050] Without limitation, the crystalline form (III) of AD-35 of the present invention has an X-ray powder diffraction spectrum as shown in FIG3 .

[0051] In addition, the infrared absorption spectrum of the crystal form (III) of AD-35 in potassium bromide is about 505.9 cm - 1 , 566.5cm -1 , 733.2cm -1 , 765.5cm -1 , 778.6cm -1 , 858.2cm -1 , 873.0cm -1 , 926.8cm -1 , 952.8cm -1 , 1037.6cm -1 , 1068.3cm -1 , 1130.8cm -1 , 1164.6cm -1 , 1246.6cm -1 , 1277.3cm -1 , 1290.5cm -1 , 1368.8cm -1 , 1411.4cm -1 , 1473.4cm -1 , 1677.5cm -1 , 2927.1cm - 1 , 3045.8cm -1 , 3420.2cm -1 .

[0052] Without limitation, the crystalline form (III) of AD-35 of the present invention has an infrared spectrum as shown in FIG10 .

[0053] The differential scanning calorimetry (DSC) spectrum of the crystal form (III) of AD-35 described in the present invention has endothermic peaks at 122±5°C and 213±5°C.

[0054] Without limitation, the crystalline form (III) of AD-35 of the present invention has a DSC spectrum as shown in FIG17 .

[0055] The TGA step weight loss of the crystalline form (III) of AD-35 described in the present invention is 10.8699%, the gas phase result shows that the main residual solvent is dichloromethane (10.6092%), and the moisture result is 0.18%, indicating that it exists in the form of dichloromethane solvate and contains 0.5 dichloromethane.

[0056] Without limitation, the crystalline form (III) of AD-35 of the present invention has a TGA spectrum as shown in FIG24 .

[0057] Another object of the present invention is to provide a method for preparing AD-35 crystalline form (III), the method comprising:

[0058] (1) Add AD-35 to a mixed solvent of methanol and dichloromethane, heat under reflux to dissolve, wherein the mass volume ratio (g / ml) of AD-35 to the mixed solvent is 1:8-18; the volume ratio (ml / g) of methanol to dichloromethane is 1:3-8;

[0059] (2) adding dichloromethane at -25 to 25°C or optionally further adding AD-35 crystal form (III) seed crystals or adding dichloromethane in which AD-35 crystal form (III) seed crystals are suspended, and standing for 48 to 96 seconds to crystallize; the volume ratio (ml / ml) of the dichloromethane to the methanol in step (1) is 1:20 to 40;

[0060] (3) Filtration to obtain the crystal form (III) of AD-35.

[0061] Another aspect of the present invention provides a crystalline form (IV) of AD-35, whose X-ray powder diffraction (XRPD) pattern has characteristic peaks at the following diffraction angles 2θ: 6.5±0.2°, 9.8±0.2°, 14.4±0.2°, 19.1±0.2°, 20.3±0.2°, and 21.4±0.2°.

[0062] Furthermore, the X-ray powder diffraction pattern of the AD-35 crystal form (IV) has characteristic peaks at the following diffraction angles 2θ: 17.7±0.2°, 21.9±0.2°, 23.4±0.2°, 25.9±0.2°, and 27.6±0.2°.

[0063] Furthermore, preferably, the X-ray powder diffraction spectrum of the crystalline form (IV) of AD-35 of the present invention has the 2θ, d and relative intensity data shown in Table 4 below:

[0064] Table 4

[0065] Without limitation, the crystalline form (IV) of AD-35 of the present invention has an X-ray powder diffraction spectrum as shown in FIG4 .

[0066] In addition, the infrared absorption spectrum of the crystal form (IV) of AD-35 in potassium bromide of the present invention is about 449.3 cm -1 , 506.7cm -1 , 533.1cm -1 , 766.1cm -1 , 778.1cm -1 , 856.7cm -1 , 870.2cm -1 , 920.0cm -1 , 936.4cm -1 , 1029.4cm -1 , 1052.3cm -1 , 1149.5cm -1 , 1162.0cm -1 , 1228.2cm -1 , 1250.7cm-1 , 1280.0cm -1 , 1320.5cm -1 , 1352.9cm -1 , 1370.2cm -1 , 1414.0cm - 1 , 1477.1cm -1 , 1599.5cm -1 , 1620.4cm -1 , 1667.9cm -1 , 2811.2cm -1 , 2864.9cm -1 , 2930.1cm -1 , 3002.8cm -1 , 3054.9cm -1 , 3218.9cm -1 , 3419.3cm -1 .

[0067] Without limitation, the crystalline form (IV) of AD-35 of the present invention has an infrared spectrum as shown in FIG11 .

[0068] The differential scanning calorimetry (DSC) spectrum of the crystal form (IV) of AD-35 of the present invention has endothermic peaks at 143±5°C, 169±5°C and 223±5°C.

[0069] Without limitation, the crystalline form (IV) of AD-35 of the present invention has a DSC spectrum as shown in FIG18 .

[0070] The TGA spectrum of the crystalline form (IV) of AD-35 described in the present invention shows two steps, with a total weight loss of 4.7402%. The gas phase results show that the main residual solvent is methanol (4.8840%), and the moisture result is 0.81%, indicating that it exists in the form of a methanol solvate and contains 0.75 methanol.

[0071] Without limitation, the crystalline form (IV) of AD-35 of the present invention has a TGA spectrum as shown in FIG25 .

[0072] Another object of the present invention is to provide a method for preparing AD-35 crystal form (IV), which is selected from any one of the following methods:

[0073] Method (1), comprising the following steps:

[0074] 1) dissolving the compound represented by Formula A in methanol or a mixed solvent of methanol and dichloromethane at room temperature; the mass volume ratio (g / ml) of the compound represented by Formula A to methanol or the mixed solvent of methanol and dichloromethane is 1:5-9; the volume ratio (ml / ml) of methanol to dichloromethane is 1:4-8;

[0075] 2) adding phosphoric acid or a methanol solution of phosphoric acid; the molar ratio of the phosphoric acid to the compound of formula A is 1:1; the volume mass ratio (ml / g) of the methanol to the compound of formula A in step (1) is 1 to 2:1;

[0076] 3) adding a poor solvent dropwise for crystallization; the poor solvent is selected from one or more of ethyl acetate, dichloromethane, ether, and acetone; the volume mass ratio (ml / g) of the poor solvent to the compound represented by formula A in step (1) is 30 to 50:1;

[0077] (4) Filtration to obtain the crystal form (IV) of AD-35.

[0078] Method (2), comprising the following steps:

[0079] (1) AD-35 is dissolved in a mixed solvent of methanol and dichloromethane, wherein the volume ratio (ml / ml) of methanol to dichloromethane is 1:4; or in a mixed solvent of methanol, water and dichloromethane, wherein the volume ratio (ml / ml) of methanol, water and dichloromethane is 10:1:80; or in a mixed solvent of methanol and water, wherein the volume ratio (ml / ml) of methanol to water is 6:1; the dissolution temperature is 20-40°C; the mass volume ratio of AD-35 to the mixed solvent is 1:18.2-35;

[0080] (2) adding a poor solvent for crystallization; the poor solvent is selected from one or more of n-heptane, dichloromethane, ethyl acetate, and isopropyl ether; the volume mass ratio (ml / g) of the poor solvent to the AD-35 in step (1) is 40 to 100:1;

[0081] (3) Filtration to obtain the crystal form (IV) of AD-35.

[0082] Method (3), comprising the following steps:

[0083] (1) Recrystallizing AD-35 by stirring under reflux in methanol; the volume mass ratio (ml / g) of methanol to AD-35 is 10 to 30;

[0084] Alternatively, AD-35 is refluxed and stirred in a mixed solvent of methanol and water for recrystallization; the volume mass ratio (ml / g) of the methanol to AD-35 is 10 to 30, and the volume mass ratio (ml / g) of the water to AD-35 is 0.5 to 1.5;

[0085] Alternatively, AD-35 is refluxed and stirred in a mixed solvent of methanol and dichloromethane for recrystallization; the volume mass ratio (ml / g) of methanol to AD-35 is 1 to 2, and the volume mass ratio (ml / g) of dichloromethane to AD-35 is 1 to 6;

[0086] (2) Cool to room temperature and filter to obtain the crystal form (IV) of AD-35.

[0087] Another aspect of the present invention provides a crystalline form (V) of AD-35, whose X-ray powder diffraction (XRPD) pattern has characteristic peaks at the following diffraction angles 2θ: 7.0±0.2°, 12.7±0.2°, 15.8±0.2°, 20.5±0.2°, 20.6±0.2°, and 22.1±0.2°.

[0088] Furthermore, the X-ray powder diffraction pattern of the crystalline form (V) of AD-35 has characteristic peaks at the following diffraction angles 2θ: 9.8±0.2°, 19.5±0.2°, 21.1±0.2°, 24.6±0.2°, and 25.7±0.2°.

[0089] Furthermore, preferably, the X-ray powder diffraction spectrum of the crystalline form (V) of AD-35 of the present invention has the 2θ, d and relative intensity data shown in Table 5 below:

[0090] Table 5

[0091] Without limitation, the crystalline form (V) of AD-35 of the present invention has an X-ray powder diffraction spectrum as shown in FIG5 .

[0092] In addition, the infrared absorption spectrum of the crystal form (V) of AD-35 in potassium bromide is about 454.5 cm -1 , 503.8cm -1 , 526.7cm -1 , 754.8cm -1 , 767.8cm -1 , 778.7cm -1 , 860.5cm -1 , 926.8cm -1 , 1034.9cm -1 , 1072.5cm -1 , 1131.8cm -1 , 1165.6cm-1 , 1250.2cm -1 , 1271.0cm - 1 , 1285.2cm -1 , 1417.5cm -1 , 1474.4cm -1 , 1598.5cm -1 , 1617.8cm -1 , 1653.5cm -1 , 2937.2cm -1 , 3002.3cm -1 , 3396.3cm -1 .

[0093] Without limitation, the crystalline form (V) of AD-35 of the present invention has an infrared spectrum as shown in FIG12 .

[0094] The differential scanning calorimetry (DSC) spectrum of the crystal form (V) of AD-35 described in the present invention has endothermic peaks at 123±5°C and 225±5°C.

[0095] Without limitation, the crystalline form (V) of AD-35 of the present invention has a DSC spectrum as shown in FIG19 .

[0096] The TGA step weight loss of the crystalline form (V) of AD-35 of the present invention is 2.48%, and the moisture result is 2.20%, indicating that it exists in the form of a hydrate and contains 0.5 water.

[0097] Without limitation, the crystalline form (V) of AD-35 of the present invention has a TGA spectrum as shown in FIG26 .

[0098] Another object of the present invention is to provide a method for preparing AD-35 crystalline form (V), the method comprising:

[0099] (1) Add AD-35 to an organic solvent selected from n-propanol, isopropanol, acetone, acetonitrile, and toluene, or a combination thereof; the mass-to-volume ratio (g / ml) of AD-35 to the organic solvent is 1:32-40; add water to dissolve the AD-35; the mass-to-volume ratio (g / ml) of AD-35 to water is 1:2-4.5;

[0100] (2) Stirring at 0-5°C for 24-48 hours;

[0101] Alternatively, add AD-35 Form (V) seed crystals at 0-5°C and stir for 4-8h;

[0102] (3) Filtration to obtain the crystal form (V) of AD-35.

[0103] Another aspect of the present invention provides a crystalline form (VI) of AD-35, whose X-ray powder diffraction (XRPD) pattern has characteristic peaks at the following diffraction angles 2θ: 6.0±0.2°, 8.8±0.2°, 14.4±0.2°, 18.5±0.2°, 19.0±0.2°, 19.5±0.2°, and 23.9±0.2°.

[0104] Furthermore, the X-ray powder diffraction pattern of the crystalline form (VI) of AD-35 has characteristic peaks at the following diffraction angles 2θ: 10.4±0.2°, 10.9±0.2°, 11.9±0.2°, 15.2±0.2°, and 22.3±0.2°.

[0105] Furthermore, preferably, the X-ray powder diffraction spectrum of the crystalline form (VI) of AD-35 of the present invention has the 2θ, d and relative intensity data shown in Table 6 below:

[0106] Table 6

[0107] Without limitation, the crystalline form (VI) of AD-35 of the present invention has an X-ray powder diffraction spectrum as shown in FIG6 .

[0108] In addition, the infrared absorption spectrum of the crystal form (VI) of AD-35 described in the present invention in potassium bromide is about 506.3 cm -1 , 566.3cm -1 , 765.7cm -1 , 777.8cm -1 , 857.4cm -1 , 873.3cm -1 , 927.1cm -1 , 952.1cm -1 , 1038.5cm -1 , 1068.8cm -1 , 1131.7cm -1 , 1163.9cm -1 , 1254.2cm -1 , 1277.6cm -1 , 1290.9cm -1 , 1368.3cm -1 , 1411.0cm -1 , 1472.9cm -1 , 1677.1cm -1 , 2926.5cm - 1 , 3443.6cm -1 .

[0109] Without limitation, the crystalline form (VI) of AD-35 of the present invention has an infrared spectrum as shown in FIG13 .

[0110] The differential scanning calorimetry (DSC) spectrum of the crystal form (VI) of AD-35 described in the present invention has a maximum endothermic peak at 215±5°C.

[0111] Without limitation, the crystalline form (VI) of AD-35 of the present invention has a DSC spectrum as shown in FIG20 .

[0112] Without limitation, the crystalline form (VI) of AD-35 of the present invention has a TGA spectrum as shown in FIG27 .

[0113] Another object of the present invention is to provide a method for preparing AD-35 crystalline form (VI), which is selected from any one of the following methods:

[0114] Method (1), comprising the following steps:

[0115] The crystal form (III) of AD-35 is heated at high temperature; the temperature of the high temperature heating is 120-150° C., and the time of the high temperature heating is 4-8 hours.

[0116] Method (2), comprising the following steps:

[0117] 1) dissolving the compound represented by formula A in ethanol; the dissolution temperature is 50-70° C.; the mass volume ratio (g / ml) of the compound represented by formula A to ethanol is 1:4-5;

[0118] 2) adding 0.5 equivalents of phosphoric acid;

[0119] 3) adding ethyl acetate dropwise and stirring to crystallize; the volume ratio of the ethyl acetate to the ethanol in step (1) is 4 to 5:1;

[0120] 4) Cool to 5-20° C. and filter to obtain the crystalline form (VI) of AD-35.

[0121] Another aspect of the present invention provides an amorphous form (VII) of AD-35, which has the diffraction peaks of the X-ray powder diffraction (XRPD) pattern shown in FIG7 .

[0122] In addition, the infrared absorption spectrum of the amorphous form (VII) of AD-35 described in the present invention in potassium bromide is about 481.4 cm -1 , 501.6cm -1 , 533.5cm -1 , 778.2cm -1 , 868.0cm -1 , 926.0cm-1 , 1034.5cm -1 , 1165.0cm -1 , 1246.3cm -1 , 1267.9cm -1 , 1318.4cm -1 , 1384.2cm -1 , 1415.6cm - 1 , 1474.2cm -1 , 1574.6cm -1 , 1652.9cm -1 , 2850.7cm -1 , 2921.5cm -1 , 3421.8cm -1 .

[0123] Without limitation, the amorphous form (VII) of AD-35 of the present invention has an infrared spectrum as shown in FIG14 .

[0124] Without limitation, the amorphous form (VII) of AD-35 of the present invention has a DSC spectrum as shown in FIG21 .

[0125] Without limitation, the amorphous form (VII) of AD-35 of the present invention has a TGA spectrum as shown in FIG28 .

[0126] Another object of the present invention is to provide a method for preparing AD-35 amorphous form (VII), which comprises:

[0127] AD-35 was dissolved in water, and the solution was vacuum dried at 40°C and -0.09 MPa.

[0128] In the present application, the dissolution and crystallization steps involved in all the above methods generally require stirring unless otherwise specified, and stirring can be performed in a known manner, such as magnetic stirring, mechanical stirring, etc.

[0129] In this application, the normal temperature or room temperature refers to the temperature range of 20°C to 25°C.

[0130] The present invention provides a pharmaceutical composition comprising an effective amount of crystalline form (I), crystalline form (II), crystalline form (III), crystalline form (IV), crystalline form (V), crystalline form (VI), or amorphous form (VII) of AD-35. The pharmaceutical composition can be administered in a common dosage form, such as an oral dosage form and an injectable dosage form, including capsules, tablets, powders, cachets, suspensions, and solutions. It is preferably administered in an oral dosage form, and more preferably in the form of tablets and capsules among the oral dosage forms.

[0131] The pharmaceutical compositions of the present invention may also contain pharmaceutically acceptable carriers or excipients. Dosage forms and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Pharmaceutically acceptable excipients and additives include non-toxic, compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents, thickeners, colorants, emulsifiers, and the like.

[0132] The present invention provides use of the crystalline form (I), crystalline form (II), crystalline form (III), crystalline form (IV), crystalline form (V), crystalline form (VI), or amorphous form (VII) of AD-35 or a pharmaceutical composition thereof in the preparation of a drug for treating Alzheimer's disease.

[0133] Advantages of the present invention: Crystal forms I, II, III, IV, V and VI have better chemical stability at 60°C than the solids obtained in Preparation Examples 1 and 2, among which Crystal form I is the most stable, and the preparation method of Crystal form III has a good impurity removal effect and can be used to solve difficult-to-remove impurities; and the six crystal forms are also less hygroscopic, which greatly facilitates the subsequent product transportation, storage or preparation process. BRIEF DESCRIPTION OF THE DRAWINGS

[0134] FIG1 is a powder X-ray diffraction pattern of the crystalline form (I) obtained in Example 1.

[0135] FIG2 is a powder X-ray diffraction pattern of Form (II) obtained in Example 29.

[0136] Figure 3 is a powder X-ray diffraction pattern of Form (III) obtained in Example 32.

[0137] Figure 4 is a powder X-ray diffraction pattern of Form (IV) obtained in Example 35.

[0138] FIG5 is a powder X-ray diffraction pattern of Form (V) obtained in Example 48.

[0139] Figure 6 is a powder X-ray diffraction pattern of Form (VI) obtained in Example 52.

[0140] Figure 7 is a powder X-ray diffraction pattern of amorphous form (VII) obtained in Example 56.

[0141] FIG8 is an infrared absorption spectrum of the crystal form (I) obtained in Example 1 in potassium bromide.

[0142] FIG9 is an infrared absorption spectrum of the crystal form (II) obtained in Example 29 in potassium bromide.

[0143] Figure 10 is the infrared absorption spectrum of Form (III) obtained in Example 32 in potassium bromide.

[0144] FIG11 is an infrared absorption spectrum of the crystalline form (IV) obtained in Example 35 in potassium bromide.

[0145] FIG12 is an infrared absorption spectrum of Form (V) obtained in Example 48 in potassium bromide.

[0146] FIG13 is an infrared absorption spectrum of Form (VI) obtained in Example 52 in potassium bromide.

[0147] Figure 14 is the infrared absorption spectrum of amorphous form (VII) obtained in Example 56 in potassium bromide.

[0148] FIG15 is a differential scanning calorimetry analysis spectrum of Form (I) obtained in Example 1.

[0149] FIG16 is a differential scanning calorimetry analysis spectrum of Form (II) obtained in Example 29.

[0150] FIG17 is a differential scanning calorimetry analysis spectrum of Form (III) obtained in Example 32.

[0151] FIG18 is a differential scanning calorimetry analysis spectrum of Form (IV) obtained in Example 35.

[0152] FIG19 is a differential scanning calorimetry analysis spectrum of Form (V) obtained in Example 48.

[0153] FIG20 is a differential scanning calorimetry analysis spectrum of Form (VI) obtained in Example 52.

[0154] FIG21 is a differential scanning calorimetry analysis spectrum of amorphous form (VII) obtained in Example 56.

[0155] Figure 22 is a thermogravimetric analysis spectrum of Form (I) obtained in Example 1.

[0156] Figure 23 is a thermogravimetric analysis spectrum of Form (II) obtained in Example 29.

[0157] Figure 24 is a thermogravimetric analysis spectrum of Form (III) obtained in Example 32.

[0158] Figure 25 is a thermogravimetric analysis spectrum of Form (IV) obtained in Example 35.

[0159] FIG26 is a thermogravimetric analysis spectrum of Form (V) obtained in Example 48.

[0160] Figure 27 is a thermogravimetric analysis spectrum of Form (VI) obtained in Example 52.

[0161] Figure 28 is a thermogravimetric analysis spectrum of amorphous (VII) obtained in Example 56.

[0162] Figure 29 is the powder X-ray diffraction pattern of AD-35 obtained in Preparation Example 1.

[0163] Figure 30 is the powder X-ray diffraction pattern of AD-35 obtained in Preparation Example 2. DETAILED DESCRIPTION

[0164] The following examples further illustrate the present invention; however, they are not intended to limit or define the scope of the invention.

[0165] The compound represented by formula A and compound AD-35 used in the method of the present invention are both prepared by referring to the preparation method disclosed in WO2017177816A1.

[0166] The solvent used in the present invention is not particularly limited, and a commercially available conventional solvent can be used.

[0167] The X-ray powder diffraction instrument and test conditions involved in the present invention are: X-ray diffraction instrument model Rigaku D / max-2200Cu target Operation method: scanning temperature 25℃, scanning speed 4° / min, scanning step width 0.01°.

[0168] The infrared spectrophotometer and test conditions involved in the present invention are as follows: infrared spectrophotometer model: BRWKER VECTOR 22; operation method: adopt KBr tablet method, scanning range 400-4000cm-1.

[0169] The DSC test conditions involved in the present invention are: DSC detector model: NETZSCH DSC 200F3; operation method: heating rate: 10°C / min, temperature range: 20-250°C.

[0170] The TGA test conditions involved in the present invention are: TGA detector model: PerkinElmer TGA 4000; operation method: heating rate: 10°C / min, temperature range: 30-250°C.

[0171] The moisture test conditions involved in the present invention are: moisture detector model: Metrohm 852Titrando+803Ti Stand; operation method: Karl Fischer volumetric moisture determination method.

[0172] It should be emphasized that the meaning or intended scope of protection of the numerical values ​​or numerical endpoints involved in the technical solution of the present invention is not limited to the numbers themselves. Those skilled in the art will understand that they include those allowable error ranges that have been widely accepted in the art, such as experimental errors, measurement errors, statistical errors and random errors, etc., and these error ranges are all included in the scope of the present invention.

[0173] Example 1: Preparation of Form (I) of AD-35

[0174] 1.0 g of the compound represented by Formula A was added to 15 ml of dichloromethane and heated to 30°C to dissolve. 0.29 g of 85% phosphoric acid dissolved in 5 ml of ethanol was then added dropwise. The mixture was stirred at 0°C for 1 hour at a stirring rate of 120 rpm. Filtering afforded 0.71 g of the desired crystalline form. The solid was blocky particles with good flowability. Its X-ray powder diffraction pattern is shown in Figure 1 ; its infrared absorption spectrum is shown in Figure 8 ; its differential scanning calorimetry analysis spectrum is shown in Figure 15 ; and its thermogravimetric analysis spectrum is shown in Figure 22 .

[0175] Example 2: Preparation of Form (I) of AD-35

[0176] 1.0 g of the compound represented by formula A was added to 20 ml of tetrahydrofuran, heated at 50° C. to dissolve, 5 ml of tetrahydrofuran solution containing 0.27 g of phosphoric acid (85%) was added dropwise, and the mixture was stirred at 5° C. for 1 h at a stirring rate of 1000 rpm. The mixture was filtered to obtain 0.80 g of the target crystalline form.

[0177] Example 3: Preparation of Form (I) of AD-35

[0178] 1.0 g of the compound represented by formula A was added to 20 ml of acetonitrile, heated at 60° C. to dissolve, 5 ml of acetonitrile solution containing 0.29 g of phosphoric acid (85%) was added dropwise, stirred at 0° C. for 2 h at a stirring rate of 60 rpm, and filtered to obtain 1.11 g of the target crystal form.

[0179] Example 4: Preparation of Form (I) of AD-35

[0180] 1.0 g of the compound represented by formula A was added to 50 ml of toluene and heated to 70°C to dissolve. 10 ml of ethanol solution containing 0.29 g of phosphoric acid (85%) was added dropwise. The mixture was stirred at -10°C for 1 h at a stirring rate of 1500 rpm and filtered to obtain 0.89 g of the target crystal form.

[0181] Example 5: Preparation of Form (I) of AD-35

[0182] 40 g of the compound represented by formula A was added to 600 ml of ethanol, heated at 70°C to dissolve, and 80 ml of methanol solution containing 11.6 g of phosphoric acid (85%) was added dropwise. Stirring was continued for 1 h. Stirring was continued for 1 h under cooling at -5°C at a stirring rate of 300 rpm. Filtering was performed to obtain 47.7 g of the target crystal form.

[0183] Example 6: Preparation of Form (I) of AD-35

[0184] 1.0 g of the compound represented by formula A was added to 10 ml of ethyl acetate and heated to 70° C. to dissolve. 5 ml of ethanol solution containing 0.30 g of phosphoric acid (85%) was added dropwise. The mixture was stirred at 30° C. for 1 h at a stirring rate of 500 rpm. The mixture was filtered to obtain 0.82 g of the target crystal form.

[0185] Example 7: Preparation of Form (I) of AD-35

[0186] 1.0 g of the compound represented by formula A was added to 100 ml of N,N-dimethylformamide and heated at 130°C to dissolve. A solution of 0.29 g of phosphoric acid (85%) dissolved in 20 ml of N,N-dimethylformamide was added dropwise. The mixture was stirred at -25°C for 3 h at a stirring rate of 800 rpm and filtered to obtain 0.98 g of the target crystalline form.

[0187] Example 8: Preparation of Form (I) of AD-35

[0188] 1.0 g of the compound represented by formula A was added to 20 ml of methanol, heated at 50°C to dissolve, 3 ml of methanol solution containing 0.29 g of phosphoric acid (85%) was added dropwise, and stirred at 0°C for 1 hour at a stirring rate of 100 rpm. Filter to obtain 0.99 g of the target crystal form.

[0189] Example 9: Preparation of Form (I) of AD-35

[0190] 1.0 g of the compound represented by formula A was added to 8 ml of chloroform, heated at 50°C to dissolve, 3 ml of ethanol solution containing 0.29 g of phosphoric acid (85%) was added dropwise, and the mixture was stirred at 10°C for 2 h at a stirring rate of 200 rpm. The mixture was filtered to obtain 0.99 g of the target crystal form.

[0191] Example 10: Preparation of Form (I) of AD-35

[0192] 1.0 g of the compound represented by formula A was added to 30 ml of acetone, heated at 50°C to dissolve, 2 ml of acetone solution containing 0.29 g of phosphoric acid (85%) was added dropwise, and the mixture was stirred at 5°C for 1 h at a stirring rate of 400 rpm. After filtering, 0.94 g of the target crystalline form was obtained.

[0193] Example 11: Preparation of Form (I) of AD-35

[0194] 1.0 g of the compound represented by formula A was added to a mixed solvent of 20 ml of ethanol, 20 ml of ethyl acetate and 10 ml of N,N-dimethylformamide, and heated at 60°C to dissolve. 15 ml of ethanol solution containing 0.29 g of phosphoric acid (85%) was added dropwise, and the mixture was stirred at 0°C for 1 h at a stirring rate of 800 rpm. Filtering gave 0.82 g of the target crystalline form.

[0195] Example 12: Preparation of Form (I) of AD-35

[0196] 0.5 g of AD-35 was added to a mixed solvent of 10 ml of ethanol and 0.9 ml of water, heated under reflux to dissolve, allowed to stand at 25° C. for 48 h for crystallization, and filtered to obtain 0.42 g of the target crystal form.

[0197] Example 13: Preparation of Form (I) of AD-35

[0198] 0.5 g of AD-35 was added to a mixed solvent of 10 ml of isopropanol and 1.25 ml of water, heated under reflux to dissolve, allowed to stand at 30° C. for 48 h for crystallization, and filtered to obtain 0.43 g of the target crystal form.

[0199] Example 14: Preparation of Form (I) of AD-35

[0200] 0.5 g of AD-35 was added to a mixed solvent of 3 ml of ethanol, 15 ml of tetrahydrofuran and 3 ml of water, heated under reflux to dissolve, allowed to stand at 20° C. for 48 h for crystallization, and filtered to obtain 0.31 g of the target crystal form.

[0201] Example 15: Preparation of Form (I) of AD-35

[0202] 0.5 g of AD-35 was added to a mixed solvent of 10 ml of acetone and 2 ml of water, heated under reflux to dissolve, allowed to stand at -25 °C for 48 h for crystallization, and filtered to obtain 0.25 g of the target crystal form.

[0203] Example 16: Preparation of Form (I) of AD-35

[0204] 0.5 g of AD-35 was added to a mixed solvent of 10 ml of n-pentanol, 7 ml of acetone and 1 ml of water, heated under reflux to dissolve, allowed to stand at 0°C for 48 h for crystallization, and filtered to obtain 0.44 g of the target crystal form.

[0205] Example 17: Preparation of Form (I) of AD-35

[0206] 0.5 g of AD-35 was added to a mixed solvent of 10 ml of n-pentanol, 5 ml of ethyl acetate, 5 ml of ethanol and 1.6 ml of water, heated under reflux to dissolve, stirred at 0°C for 6 h, and filtered to obtain 0.38 g of the target crystal form.

[0207] Example 18: Preparation of Form (I) of AD-35

[0208] 0.5 g of AD-35 was added to a mixed solvent of 30 ml of n-butanol and 3 ml of water, heated under reflux to dissolve, and stirred at 5°C for 6 h to obtain 0.34 g of the target crystal form.

[0209] Example 19: Preparation of Form (I) of AD-35

[0210] 0.5 g of AD-35 was added to a mixed solvent of 10 ml of N,N-dimethylformamide and 0.5 ml of water, heated under reflux to dissolve, stirred at 30° C. for 48 h, and filtered to obtain 0.45 g of the target crystal form.

[0211] Example 20: Preparation of Form (I) of AD-35

[0212] 0.5 g of AD-35 was added to a mixed solvent of 20 ml of N,N-dimethylformamide and 3 ml of water, heated under reflux to dissolve, 20 ml of methyl tert-butyl ether was added dropwise under stirring at 30°C for crystallization, and filtered to obtain 0.42 g of the target crystal form.

[0213] Example 21: Preparation of Form (I) of AD-35

[0214] 0.5 g of AD-35 was added to a mixed solvent of 1 ml of ethanol, 0.2 ml of water and 4 ml of dichloromethane, heated under reflux to dissolve, 31.2 ml of isopropanol was added dropwise under stirring at -25°C for crystallization, and filtered to obtain 0.39 g of the target crystal form.

[0215] Example 22: Preparation of Form (I) of AD-35

[0216] 1.0 g of AD-35 was added to a mixed solvent of 20 ml of acetonitrile, 20 ml of N,N-dimethylformamide and 6 ml of water, heated under reflux to dissolve, 23 ml of tetrahydrofuran was added dropwise under stirring at 20°C for crystallization, and filtered to obtain 0.78 g of the target crystal form.

[0217] Example 23: Preparation of Form (I) of AD-35

[0218] 0.5 g of AD-35 was added to a mixed solvent of 10 ml of dimethyl sulfoxide, 5 ml of ethanol and 0.5 ml of water, heated under reflux to dissolve, 20 ml of ethyl acetate was added dropwise at 0°C with stirring for crystallization, and filtered to obtain 0.42 g of the target crystal form.

[0219] Example 24: Preparation of Form (I) of AD-35

[0220] 1.0 g of the AD-35 crystal form (IV) was added to 20 ml of ethanol, refluxed at 80° C. with stirring for 4 h, cooled to room temperature, and filtered to obtain 0.92 g of the target crystal form.

[0221] Example 25: Preparation of Form (I) of AD-35

[0222] 1.0 g of the AD-35 crystal form (V) was added to 50 ml of ethanol, stirred at 40° C. for 48 h, cooled to room temperature, and filtered to obtain 0.86 g of the target crystal form.

[0223] Example 26: Preparation of Form (I) of AD-35

[0224] 1.0 g of amorphous form (VII) of AD-35 was added to 20 ml of ethanol, stirred at 60° C. for 12 h, cooled to room temperature, and filtered to obtain 0.85 g of the target crystalline form.

[0225] Example 27: Preparation of Form (I) of AD-35

[0226] 0.5 g of the crystal form (IV) of AD-35 was spread on a watch glass and heated at 120° C. for 7 h to obtain 0.47 g of the target crystal form.

[0227] Example 28: Preparation of Form (I) of AD-35

[0228] 0.5 g of the AD-35 crystal form (V) was spread on a watch glass and heated at 200° C. for 3 h to obtain 0.44 g of the target crystal form.

[0229] The X-ray powder diffraction pattern of the crystalline form (I) of AD-35 obtained in Example 2-28 is consistent with the X-ray powder diffraction pattern of the crystalline form (I) of AD-35 in Example 1.

[0230] Example 29: Preparation of Form (II) of AD-35

[0231] 17.4 g of the compound represented by Formula A was added to 87 ml of ethanol and heated to 70°C for dissolution. 4.2 g of 85% phosphoric acid was added at 180 rpm, followed by dropwise addition of 87 ml of ethyl acetate. The mixture was cooled to room temperature and filtered to yield 18.4 g of the desired crystalline form. The solid particles were agglomerated. The X-ray powder diffraction pattern is shown in Figure 2 ; the infrared absorption spectrum is shown in Figure 9 ; the differential scanning calorimetry analysis spectrum is shown in Figure 16 ; and the thermogravimetric analysis spectrum is shown in Figure 23 .

[0232] Example 30: Preparation of Form (II) of AD-35

[0233] 5.0 g of the compound represented by formula A was added to 20 ml of isopropanol, heated at 65° C. to dissolve, 0.57 g of phosphoric acid (85%) was added at a rotation speed of 100 rpm, 40 ml of ethyl acetate was added dropwise, and the mixture was cooled to room temperature and filtered to obtain 2.18 g of the target crystal form.

[0234] Example 31: Preparation of Form (II) of AD-35

[0235] 5.0 g of the compound represented by formula A was added to 30 ml of n-butanol, heated at 50° C. to dissolve, 0.57 g of phosphoric acid (85%) was added at a rotation speed of 10 rpm, 50 ml of ethyl acetate was added dropwise, and the mixture was cooled to room temperature and filtered to obtain 2.01 g of the target crystal form.

[0236] The X-ray powder diffraction patterns of the crystalline form (II) of AD-35 obtained in Examples 30 and 31 are consistent with the X-ray powder diffraction pattern of the crystalline form (II) of AD-35 in Example 29.

[0237] Example 32: Preparation of Form (III) of AD-35

[0238] 2.0g of AD-35 was added to a mixture of 4ml of methanol and 32ml of dichloromethane, heated under reflux to dissolve. 160ml of dichloromethane was added at -25°C, and the mixture was allowed to stand at -25°C for 48 hours to crystallize. Filtering yielded 1.91g of the target crystalline form, which was needle-shaped and flocculent. Its X-ray powder diffraction pattern is shown in Figure 3; its infrared absorption spectrum is shown in Figure 10; its differential scanning calorimetry analysis spectrum is shown in Figure 17; and its thermogravimetric analysis spectrum is shown in Figure 24.

[0239] Example 33: Preparation of Form (III) of AD-35

[0240] 5.0 g of AD-35 was added to a mixed solvent of 15 ml of methanol and 45 ml of dichloromethane, heated under reflux to dissolve, 450 ml of dichloromethane was added at 0°C, a small amount of Form III seed crystals was added, the mixture was allowed to stand for 72 h, and filtered to obtain 4.83 g of the target crystal form.

[0241] Example 34: Preparation of Form (III) of AD-35

[0242] 20.0 g of AD-35 was added to a mixed solvent of 40 ml of methanol and 120 ml of dichloromethane, heated under reflux to dissolve, 800 ml of dichloromethane suspended with a small amount of Form III seed crystals was added at 25°C, and the mixture was allowed to stand at 25°C for 96 h for crystallization. After filtration, 20.7 g of the target crystalline form was obtained.

[0243] The X-ray powder diffraction patterns of the crystalline form (III) of AD-35 obtained in Examples 33 and 34 are consistent with the X-ray powder diffraction pattern of the crystalline form (III) of AD-35 in Example 32.

[0244] Example 35: Preparation of Form (IV) of AD-35

[0245] At room temperature, 1.0 g of the compound represented by Formula A was dissolved in 8 ml of methanol. 0.29 g of 85% phosphoric acid was added, and 40 ml of ethyl acetate was added dropwise for crystallization. Filtering yielded 0.82 g of the desired crystalline form as large, blocky particles. Its X-ray powder diffraction pattern is shown in Figure 4 ; its infrared absorption spectrum is shown in Figure 11 ; its differential scanning calorimetry analysis spectrum is shown in Figure 18 ; and its thermogravimetric analysis spectrum is shown in Figure 25 .

[0246] Example 36: Preparation of Form (IV) of AD-35

[0247] At room temperature, 1.0 g of the compound represented by formula A was dissolved in a mixed solvent of 1 ml of methanol and 8 ml of dichloromethane. 1 ml of a methanol solution containing 0.29 g of phosphoric acid (85%) was added. 30 ml of dichloromethane was added dropwise for crystallization. The mixture was filtered to obtain 0.94 g of the target crystalline form.

[0248] Example 37: Preparation of Form (IV) of AD-35

[0249] At room temperature, 1.0 g of the compound represented by formula A was dissolved in a mixed solvent of 1 ml of methanol and 4 ml of dichloromethane. 2 ml of a methanol solution containing 0.29 g of 85% phosphoric acid was added. A mixed solution of 30 ml of ether and 20 ml of acetone was added dropwise for crystallization. The mixture was filtered to obtain 1.12 g of the target crystalline form.

[0250] Example 38: Preparation of Form (IV) of AD-35

[0251] 0.5 g of AD-35 was added to a mixed solvent of 1 ml of methanol, 0.1 ml of water and 8 ml of dichloromethane, stirred and dissolved at 30° C. 40 ml of n-heptane was added dropwise at 30° C. for crystallization, and filtered to obtain 0.45 g of the target crystal form.

[0252] Example 39: Preparation of Form (IV) of AD-35

[0253] 0.5 g of AD-35 was added to a mixed solvent of 1 ml of methanol, 0.1 ml of water and 8 ml of dichloromethane, stirred and dissolved at 25° C. 40 ml of dichloromethane was added dropwise, and the mixture was filtered to obtain 0.49 g of the target crystal form.

[0254] Example 40: Preparation of Form (IV) of AD-35

[0255] 0.5 g of AD-35 was added to a mixed solvent of 2 ml of methanol and 8 ml of dichloromethane, stirred and dissolved at 20° C. 50 ml of ethyl acetate was added dropwise for crystallization, and filtered to obtain 0.45 g of the target crystal form.

[0256] Example 41: Preparation of Form (IV) of AD-35

[0257] 1.0 g of AD-35 was added to a mixed solvent of 30 ml of methanol and 5 ml of water, heated at 40° C. to dissolve, 40 ml of isopropyl ether was added dropwise for crystallization, and filtered to obtain 0.98 g of the target crystal form.

[0258] Example 42: Preparation of Form (IV) of AD-35

[0259] 1.0 g of AD-35 was added to 10 ml of methanol, refluxed and stirred for 2 h, cooled to room temperature, and filtered to obtain 0.70 g of the target crystal form.

[0260] Example 43: Preparation of Form (IV) of AD-35

[0261] 1.0 g of AD-35 was added to 30 ml of methanol, refluxed and stirred for 1.5 h, cooled to room temperature, and filtered to obtain 0.50 g of the target crystal form.

[0262] Example 44: Preparation of Form (IV) of AD-35

[0263] 1.0 g of AD-35 was added to a mixed solvent of 10 ml of methanol and 0.5 ml of water, refluxed and stirred for 2 h, cooled to room temperature, and filtered to obtain 0.38 g of the target crystal form.

[0264] Example 45: Preparation of Form (IV) of AD-35

[0265] 1.0 g of AD-35 was added to a mixed solvent of 30 ml of methanol and 1.5 ml of water, refluxed and stirred for 2 h, cooled to room temperature, and filtered to obtain 0.24 g of the target crystal form.

[0266] Example 46: Preparation of Form (IV) of AD-35

[0267] 10.0 g of AD-35 was added to a mixed solvent of 10 ml of methanol and 60 ml of dichloromethane, dissolved under reflux, stirred for 1 h, cooled to room temperature, and filtered to obtain 3.8 g of the target crystal form.

[0268] Example 47: Preparation of Form (IV) of AD-35

[0269] 10.0 g of AD-35 was added to a mixed solvent of 20 ml of methanol and 10 ml of dichloromethane, refluxed and stirred for 2 h, cooled to room temperature, and filtered to obtain 4.1 g of the target crystal form.

[0270] The X-ray powder diffraction patterns of the crystalline form (IV) of AD-35 obtained in Examples 36-47 are consistent with the X-ray powder diffraction pattern of the crystalline form (IV) of AD-35 in Example 35.

[0271] Example 48: Preparation of Form (V) of AD-35

[0272] 0.5g of AD-35 was added to a mixture of 10ml of n-propanol and 10ml of toluene, dissolved in 1ml of water, stirred at 0°C for 24h to crystallize, and filtered to yield 0.41g of the target crystalline form as blocky particles. Its X-ray powder diffraction pattern is shown in Figure 5; its infrared absorption spectrum is shown in Figure 12; its differential scanning calorimetry analysis spectrum is shown in Figure 19; and its thermogravimetric analysis spectrum is shown in Figure 26.

[0273] Example 49: Preparation of Form (V) of AD-35

[0274] 4.0 g of AD-35 was added to a mixed solvent of 80 ml of n-propanol and 80 ml of toluene, and 8 ml of water was added to dissolve it. Form V seed crystals (Form V prepared in Example 48) were added at 0° C. and stirred for 8 h. The mixture was filtered to obtain 3.1 g of the target crystal form.

[0275] Example 50: Preparation of Form (V) of AD-35

[0276] 1.0 g of AD-35 was added to a mixed solvent of 20 ml of isopropanol and 20 ml of toluene, and 3 ml of water was added to dissolve it. Form V seed crystals (Form V prepared in Example 48) were added at 5° C. and stirred for 6 h. The mixture was filtered to obtain 0.74 g of the target crystal form.

[0277] Example 51: Preparation of Form (V) of AD-35

[0278] 1.0 g of AD-35 was added to a mixed solvent of 2 ml of acetone and 30 ml of acetonitrile, and 4.5 ml of water was added to dissolve it. Form V seed crystals (Form V prepared in Example 48) were added at 0°C and stirred for 4 h. The mixture was filtered to obtain 0.56 g of the target crystal form.

[0279] The X-ray powder diffraction patterns of the crystalline form (V) of AD-35 obtained in Examples 49-51 are consistent with the X-ray powder diffraction patterns of the crystalline form (V) of AD-35 in Example 48.

[0280] Example 52: Preparation of Form (VI) of AD-35

[0281] 6.0 g of Form (III) AD-35 was spread on a watch glass and heated at 150°C for 4 hours to yield 5.27 g of the desired crystalline form. Its X-ray powder diffraction pattern is shown in Figure 6 ; its infrared absorption spectrum is shown in Figure 13 ; its differential scanning calorimetry analysis pattern is shown in Figure 20 ; and its thermogravimetric analysis pattern is shown in Figure 27 .

[0282] Example 53: Preparation of Form (VI) of AD-35

[0283] 6.0 g of the crystal form (III) of AD-35 was spread on a watch glass and heated at 120° C. for 8 h to obtain 5.18 g of the target crystal form.

[0284] Example 54: Preparation of Form (VI) of AD-35

[0285] 2.0 g of the compound represented by formula A was added to 10 ml of ethanol, heated in a water bath at 50°C with stirring until the solid was completely dissolved. 0.29 g of phosphoric acid (85%) was slowly added. After 3 minutes, solid began to precipitate. 40 ml of ethyl acetate was added dropwise, and stirring was continued for 3 hours. The mixture was cooled to 5°C and filtered to obtain 1.20 g of the target crystalline form. The solid was needle-shaped and flocculent.

[0286] Example 55: Preparation of Form (VI) of AD-35

[0287] 2.0 g of the compound represented by formula A was added to 8 ml of ethanol, heated in a water bath at 70°C with stirring until the solid was completely dissolved. 0.29 g of phosphoric acid (85%) was slowly added. After 3 minutes, solid began to precipitate. 40 ml of ethyl acetate was added dropwise, and stirring was continued for 3 hours. The mixture was cooled to 20°C and filtered to obtain 1.30 g of the target crystalline form.

[0288] The X-ray powder diffraction patterns of the crystalline form (VI) of AD-35 obtained in Examples 53-55 are consistent with the X-ray powder diffraction pattern of the crystalline form (VI) of AD-35 in Example 52.

[0289] Example 56: Preparation of Amorphous Form (VII) of AD-35

[0290] At room temperature, 2.0 g of AD-35 was completely dissolved in 20 ml of water. The solution was then dried under vacuum at 40°C for 72 hours to yield 2.01 g of the desired crystalline form. Its X-ray powder diffraction pattern is shown in Figure 7 ; its infrared absorption spectrum is shown in Figure 14 ; its differential scanning calorimetry analysis pattern is shown in Figure 21 ; and its thermogravimetric analysis pattern is shown in Figure 28 .

[0291] Preparation Example 1: Preparation of AD-35 according to patent WO2014005421A1

[0292] To a reaction flask were added 2 g (0.049 mol) of the compound of formula A and 40 ml of ethanol. The mixture was heated and stirred at 60°C until completely dissolved. 0.57 g (0.049 mol) of 85% phosphoric acid was added and stirred to precipitate a colloidal solid. 40 ml of ethyl acetate was added dropwise, and the mixture was cooled to room temperature and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with a small amount of ethyl acetate and dried to obtain 2.1 g of compound AD-35. Its X-ray powder diffraction pattern is shown in Figure 29, which is different from AD-35 Forms I to VI.

[0293] Preparation Example 2: Preparation of AD-35 according to patent WO2017177816A1

[0294] To a 50 mL reaction flask, 2 g (4.9 mmol) of compound A and 40 mL of ethanol were added, and the mixture was heated at 60°C to dissolve. 0.57 g (4.9 mmol) of 85% phosphoric acid was added with stirring to precipitate a colloidal solid. 40 mL of ethyl acetate was added dropwise, and the mixture was cooled to room temperature and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with a small amount of ethyl acetate. The mixture was dried to obtain 2.3 g of an off-white colloidal solid. Its X-ray powder diffraction pattern is shown in Figure 30, which is different from those in Preparation Example 1 and AD-35 Forms I to VI.

[0295] Finally, the present invention provides residual solvent analysis of some AD-35 crystal forms, as well as stability and hygroscopicity studies of AD-35 crystal forms. The results are as follows:

[0296] (1) Residual solvent analysis

[0297] (Measurement method and conditions)

[0298] Take the crystalline form III prepared in Example 32 and the crystalline form IV prepared in Example 35, measure the residual amount of methanol and dichloromethane in each sample under the following conditions, and calculate the average of the two results.

[0299] result:

[0300] From the above results, it is clear that the residual solvent of Form (III) is mainly dichloromethane, and the residual solvent of Form (IV) is mainly methanol. Combined with the results of thermogravimetric analysis and differential scanning calorimetry analysis, Form (III) is a dichloromethane solvate, and Form (IV) is a methanol solvate.

[0301] (2) Stability determination

[0302] Form I prepared in Example 1, Form II prepared in Example 29, Form III prepared in Example 32, Form IV prepared in Example 35, Form V prepared in Example 48, Form VI prepared in Example 52, the sample obtained in Preparation Example 1, and the sample obtained in Preparation Example 2 were subjected to stability testing at 60°C for 10 days. The HPLC purity and maximum single impurity content of the compounds were tested before and after storage, and the crystal form after 10 days at 60°C was tested. The results are shown in the table below:

[0303] (Measurement method and conditions)

[0304] Accurately weigh 50 mg of each crystalline form sample at each temperature into a 50 mL brown volumetric flask and dilute to volume with diluent. Measure the impurity content of each sample under the following conditions.

[0305] result:

[0306] From the stability data at 60°C for 10 days in the table above, it can be seen that after 10 days, the HPLC purity and maximum impurity content of Forms I, II, III, IV, V, and VI changed little, indicating that the chemical stability of the crystal forms was excellent. The change in HPLC purity of the solids obtained in Preparation Examples 1 and 2 was greater than that of Forms I to VI, and the change in HPLC purity of the solids obtained in Preparation Examples 1 and 2 was the largest. Therefore, the chemical stability of Forms I to VI was superior to that of the solids obtained in Preparation Examples 1 and 2. After 10 days at 60°C, Forms I, II, and VI were stable, while Forms III, IV, V, and the solids obtained in Preparation Examples 1 and 2 showed changes in their crystal form.

[0307] (3) Hygroscopicity determination

[0308] Take a dry glass weighing bottle with a stopper and place it in a suitable constant temperature sealed container at 25℃±1℃ the day before the experiment (place a saturated sodium chloride solution at the bottom with a relative humidity of 75%±2%; or a saturated ammonium sulfate solution at a relative humidity of 80%±2%; or a saturated potassium nitrate solution at a relative humidity of 92.5%±2%), and accurately weigh the weight (M1).

[0309] Take an appropriate amount of the test sample and spread it evenly in the above-mentioned weighing bottle. The thickness of the test sample is generally about 1mm, and accurately weigh the weight (M2).

[0310] Open the weighing bottle and place it under the above-mentioned constant temperature and humidity conditions with the bottle cap on for 24 hours; cover the weighing bottle cap and accurately weigh the weight (M3).

[0311] Calculation formula:

[0312] result: Note: During the hygroscopicity test of Form III, dichloromethane evaporates and the mass decreases. Therefore, the hygroscopicity of Form III is determined by the following method.

[0313] Supplementary experiments:

[0314] 1) Take 0.1 g of Form III test sample and determine the water content (%) in the sample by Karl Fischer volumetric water determination method. Each sample is measured twice on average, and the average value W1 is calculated.

[0315] 2) 0.1 g of each Form III sample obtained at three different humidity levels (75% ± 2%, 80% ± 2%, and 92.5% ± 2%) in the hygroscopicity experiment was taken and the water content (%) of the sample was determined by Karl Fischer volumetric determination. Each sample was measured twice on average to calculate the average value W2.

[0316] 3) Percentage weight gain (%) = W2 - W1.

[0317] result:

[0318] The results show that at relative humidity of 75% ± 2% and 80% ± 2%, AD-35 Forms I, II, III, and VI are almost non-hygroscopic (almost non-hygroscopic < 0.2%). At a relative humidity of 92.5% ± 2%, AD-35 Forms I, II, and III are slightly hygroscopic (0.2% ≤ hygroscopic < 2%). Since Form III is a dichloromethane solvate, it loses dichloromethane under these humidity conditions, resulting in a mass loss. Form IV is almost non-hygroscopic at a relative humidity of 75% ± 2%, but is slightly hygroscopic at a relative humidity of 80% ± 2% and hygroscopic at a relative humidity of 92.5% ± 2%. Whether under relative humidity conditions of 75% ± 2% and 80% ± 2%, or under relative humidity conditions of 92.5% ± 2%, Form V and the solids obtained from Preparation Examples 1 and 2 were all hygroscopic (2% ≤ hygroscopic < 15%), but the hygroscopicity of Form V was lower than that of the solids obtained from Preparation Examples 1 and 2. The hygroscopicity of AD-35 Forms I to VI and the solids obtained from Preparation Examples 1 and 2 increased with increasing humidity, and the hygroscopicity of AD-35 Forms I to VI was significantly better than that of the solids obtained from Preparation Examples 1 and 2.

Claims

1. A crystalline form (I) of 6-[2-[1-(2-pyridylmethyl)-4-piperidinyl]ethyl]spiro[[1,3]dioxol[4,5-f]isoindole-7,1'-cyclopropane]-5-one phosphate (AD-35) having the following structure, It is characterized in that Its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 7.2±0.2°, 7.8±0.2°, 14.2±0.2°, 16.1±0.2°, 16.5±0.2°, 21.0±0.2°, and 23.5±0.2°.

2. The AD-35 crystal form (I) according to claim 1, characterized in that Its X-ray powder diffraction pattern further has characteristic peaks at the following diffraction angles 2θ: 12.8±0.2°, 16.7±0.2°, 17.6±0.2°, 18.7±0.2°, 19.3±0.2°, 20.0±0.2°, 21.7±0.2°, 24.1±0.2°, 26.6±0.2°.

3. The AD-35 crystal form (I) according to claim 1 or 2, characterized in that The crystal form (I) has an X-ray powder diffraction pattern as shown in FIG1 .

4. Form (II) of AD-35, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 6.8±0.2°, 12.7±0.2°, 16.6±0.2°, 20.2±0.2°, 20.8±0.2°, and 22.6±0.2°.

5. The AD-35 crystal form (II) according to claim 4, characterized in that Its X-ray powder diffraction pattern further has characteristic peaks at the following diffraction angles 2θ: 13.8±0.2°, 19.6±0.2°, 20.0±0.2°, 24.7±0.2°, 28.0±0.2°.

6. The AD-35 crystal form (II) according to claim 4 or 5, characterized in that The crystal form (II) has an X-ray powder diffraction pattern as shown in FIG2 .

7. Form (III) of AD-35, characterized in that Its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 9.2±0.2°, 18.2±0.2°, 18.5±0.2°, 20.4±0.2°, and 23.9±0.2°.

8. The AD-35 crystal form (III) according to claim 7, characterized in that Its X-ray powder diffraction pattern further has characteristic peaks at the following diffraction angles 2θ: 11.5±0.2°, 15.4±0.2°, 19.0±0.2°, 22.1±0.2°, 25.9±0.2°, 26.8±0.2°.

9. The AD-35 crystal form (III) according to claim 7 or 8, characterized in that The crystal form (III) has an X-ray powder diffraction pattern as shown in FIG3 .

10. Form (IV) of AD-35, characterized in that Its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 6.5±0.2°, 9.8±0.2°, 14.4±0.2°, 19.1±0.2°, 20.3±0.2°, and 21.4±0.2°.

11. The AD-35 crystal form (IV) according to claim 10, characterized in that Its X-ray powder diffraction pattern further has characteristic peaks at the following diffraction angles 2θ: 17.7±0.2°, 21.9±0.2°, 23.4±0.2°, 25.9±0.2°, 27.6±0.2°.

12. The AD-35 crystal form (IV) according to claim 10 or 11, characterized in that The crystal form (IV) has an X-ray powder diffraction pattern as shown in FIG4 .

13. Form (V) of AD-35, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 7.0±0.2°, 12.7±0.2°, 15.8±0.2°, 20.5±0.2°, 20.6±0.2°, and 22.1±0.2°.

14. The AD-35 crystal form (V) according to claim 13, characterized in that Its X-ray powder diffraction pattern further has characteristic peaks at the following diffraction angles 2θ: 9.8±0.2°, 19.5±0.2°, 21.1±0.2°, 24.6±0.2°, 25.7±0.2°.

15. The AD-35 crystalline form (V) according to claim 13 or 14, characterized in that: The crystal form (V) has an X-ray powder diffraction pattern as shown in FIG5 .

16. Form (VI) of AD-35, characterized in that Its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 6.0±0.2°, 8.8±0.2°, 14.4±0.2°, 18.5±0.2°, 19.0±0.2°, 19.5±0.2°, and 23.9±0.2°.

17. The AD-35 crystal form (VI) according to claim 16, characterized in that Its X-ray powder diffraction pattern further has characteristic peaks at the following diffraction angles 2θ: 10.4±0.2°, 10.9±0.2°, 11.9±0.2°, 15.2±0.2°, 22.3±0.2°.

18. The AD-35 crystal form (VI) according to claim 16 or 17, characterized in that The crystal form (VI) has an X-ray powder diffraction pattern as shown in FIG6 .

19. A method for preparing the AD-35 crystalline form (I) according to any one of claims 1 to 3, wherein the method is selected from any one of the following methods: The method (1) comprises the following steps: 1) dissolving the compound represented by formula A in an organic solvent a; the dissolving temperature is 30 to 130° C., preferably 40 to 90° C.; the organic solvent a is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, toluene, ethanol, ethyl acetate, N,N-dimethylformamide, methanol, chloroform, and acetone; the volume mass ratio (ml / g) of the organic solvent a to the compound represented by formula A is 8 to 100:1, preferably 10 to 50:1; 2) adding phosphoric acid in an organic solvent b dropwise; the molar ratio of the phosphoric acid to the compound of formula A is 0.95-1.05:1, and the organic solvent b is selected from one or more of ethanol, tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, and acetone; the volume mass ratio (ml / g) of the organic solvent b to the compound of formula A is 2-20:1; 3) stirring and crystallizing; the stirring rate is 60 to 1500 rpm, preferably 120 to 1000 rpm; the crystallization temperature is -25 to 30°C; 4) filtering to obtain the crystalline form (I) of AD-35; Method (2), comprising the following steps: 1) Add AD-35 to a mixed solvent of an organic solvent and water, and heat under reflux to dissolve; the mass volume ratio (g / ml) of the AD-35 to the mixed solvent is 1:10.4-66; the volume ratio of the organic solvent to water is 5-30:1; the organic solvent is selected from one or more of ethanol, isopropanol, tetrahydrofuran, acetone, n-pentanol, ethyl acetate, n-butanol, N,N-dimethylformamide, dichloromethane, acetonitrile, and dimethyl sulfoxide; 2) standing or stirring at -25 to 30°C for crystallization; or, adding an organic solvent dropwise at -25 to 30°C for crystallization; the organic solvent is selected from one or more of methyl tert-butyl ether, isopropanol, tetrahydrofuran, and ethyl acetate; the volume ratio (ml / g) of the organic solvent to the mixed solvent in step (1) is 0.5 to 6:1; 3) filtering to obtain the crystalline form (I) of AD-35; Method (3), comprising the following steps: The AD-35 crystal form (IV) according to any one of claims 10 to 12, or the AD-35 crystal form (V) according to any one of claims 13 to 15, or the AD-35 amorphous form (VII) is stirred in ethanol at 40 to 80° C. for 4 h to 48 h, cooled to room temperature, and filtered to obtain the AD-35 crystal form (I); the mass volume ratio (g / ml) of the AD-35 to ethanol is 1:20 to 50; Method (4), comprising the following steps: The AD-35 crystal form (IV) described in any one of claims 10 to 12, or the AD-35 crystal form (V) described in any one of claims 13 to 15 is heated at high temperature for 3h to 7h to obtain the AD-35 crystal form (I), wherein the high temperature heating temperature is 120°C to 200°C.

20. A method for preparing the AD-35 crystalline form (II) according to any one of claims 4 to 6, characterized in that: The method comprises: (1) dissolving the compound represented by formula A in an alcohol solvent; the dissolution temperature is 50-70° C.; the mass volume ratio (g / ml) of the compound A to the alcohol solvent is 1:4-6; the alcohol solvent is a C2-C4 alcohol, preferably ethanol and isopropanol; (2) adding phosphoric acid under stirring; the molar ratio of the phosphoric acid to the compound of formula A is 0.4 to 0.85:1; the stirring rate is 10 to 180 rpm; (3) adding ethyl acetate dropwise; the volume ratio (ml / g) of the alcohol solvent to ethyl acetate in step (1) is 1:1-2; (4) Filtration to obtain the crystal form (II) of AD-35.

21. A method for preparing the AD-35 crystalline form (III) according to any one of claims 7 to 9, characterized in that: The method comprises: (1) Adding AD-35 to a mixed solvent of methanol and dichloromethane, heating and refluxing to dissolve, wherein the mass volume ratio (g / ml) of AD-35 to the mixed solvent is 1:8-18; the volume ratio (ml / g) of methanol to dichloromethane is 1:3-8; (2) adding dichloromethane at -25 to 25°C or optionally further adding the seed crystals of the AD-35 crystal form (III) according to any one of claims 7 to 9 or adding dichloromethane in which the seed crystals of the AD-35 crystal form (III) according to any one of claims 7 to 9 are suspended, and standing for 48 to 96 hours for crystallization; the volume ratio (ml / ml) of the dichloromethane to the methanol in step (1) is 1:20 to 40; (3) Filtration to obtain the crystalline form (III) of AD-35.

22. A method for preparing the AD-35 crystalline form (IV) according to any one of claims 10 to 12, the method being selected from any one of the following methods: The method (1) comprises the following steps: 1) dissolving the compound represented by formula A in methanol or a mixed solvent of methanol and dichloromethane at room temperature; the mass volume ratio (g / ml) of the compound represented by formula A to methanol or a mixed solvent of methanol and dichloromethane is 1:5-9; the volume ratio (ml / ml) of methanol to dichloromethane is 1:4-8; 2) adding phosphoric acid or a methanol solution of phosphoric acid; the molar ratio of the phosphoric acid to the compound of formula A is 1:1; the volume mass ratio (ml / g) of the methanol to the compound of formula A in step (1) is 1-2:1; 3) adding a poor solvent dropwise for crystallization; the poor solvent is selected from one or more of ethyl acetate, dichloromethane, ether, and acetone; the volume mass ratio (ml / g) of the poor solvent to the compound represented by formula A in step (1) is 30 to 50:1; (4) filtering to obtain the crystalline form (IV) of AD-35; Method (2), comprising the following steps: (1) dissolving AD-35 in a mixed solvent of methanol and dichloromethane, wherein the volume ratio (ml / ml) of methanol to dichloromethane is 1:4; or dissolving AD-35 in a mixed solvent of methanol, water and dichloromethane, wherein the volume ratio (ml / ml) of methanol, water and dichloromethane is 10:1:80; or dissolving AD-35 in a mixed solvent of methanol and water, wherein the volume ratio (ml / ml) of methanol to water is 6:1; the dissolution temperature is 20 to 40°C; the mass volume ratio of AD-35 to the mixed solvent is 1:18.2 to 35; (2) adding a poor solvent for crystallization; the poor solvent is selected from one or more of n-heptane, dichloromethane, ethyl acetate, and isopropyl ether; the volume mass ratio (ml / g) of the poor solvent to the AD-35 in step (1) is 40 to 100:1; (3) filtering to obtain the crystalline form (IV) of AD-35; Method (3), comprising the following steps: (1) Recrystallizing AD-35 by reflux stirring in methanol; the volume mass ratio (ml / g) of methanol to AD-35 is 10 to 30; Alternatively, AD-35 is refluxed and stirred in a mixed solvent of methanol and water for recrystallization; the volume mass ratio (ml / g) of methanol to AD-35 is 10 to 30, and the volume mass ratio (ml / g) of water to AD-35 is 0.5 to 1.5; Alternatively, AD-35 is refluxed and stirred in a mixed solvent of methanol and dichloromethane for recrystallization; the volume mass ratio (ml / g) of methanol to AD-35 is 1 to 2, and the volume mass ratio (ml / g) of dichloromethane to AD-35 is 1 to 6; (2) Cool to room temperature and filter to obtain the crystalline form (IV) of AD-35.

23. A method for preparing the AD-35 crystalline form (V) according to any one of claims 13 to 15, characterized in that: The method comprises: (1) Add AD-35 to an organic solvent selected from the group consisting of n-propanol, isopropanol, acetone, acetonitrile, and toluene, wherein the mass volume ratio (g / ml) of AD-35 to the organic solvent is 1:32 to 40; add water to dissolve the AD-35; wherein the mass volume ratio (g / ml) of AD-35 to water is 1:2 to 4.5; (2) Stirring at 0-5°C for 24-48 hours; Alternatively, adding the AD-35 crystal form (V) seed crystals according to any one of claims 13 to 15 and stirring for 4 to 8 hours at 0 to 5°C; (3) Filtration to obtain the crystalline form (V) of AD-35.

24. A method for preparing the AD-35 crystalline form (VI) according to any one of claims 16 to 18, the method being selected from any one of the following methods: The method (1) comprises the following steps: High temperature heating of the crystalline form (III) of AD-35 according to any one of claims 7 to 9; the temperature of the high temperature heating is 120 to 150° C., and the time of the high temperature heating is 4 to 8 hours; Method (2), comprising the following steps: 1) dissolving the compound represented by formula A in ethanol; the dissolving temperature is 50-70° C.; the mass volume ratio (g / ml) of the compound represented by formula A to ethanol is 1:4-5; 2) Add 0.5 equivalent of phosphoric acid; 3) adding ethyl acetate dropwise and stirring to crystallize; the volume ratio of the ethyl acetate to the ethanol in step (1) is 4 to 5:1; 4) Cool to 5-20°C and filter to obtain the crystalline form (VI) of AD-35.

25. A pharmaceutical composition comprising an effective amount of the crystalline form (I) of AD-35 described in any one of claims 1 to 3, the crystalline form (II) of AD-35 described in any one of claims 4 to 6, the crystalline form (III) of AD-35 described in any one of claims 7 to 9, the crystalline form (IV) of AD-35 described in any one of claims 10 to 12, the crystalline form (V) of AD-35 described in any one of claims 13 to 15, or the crystalline form (VI) of AD-35 described in any one of claims 16 to 18.

26. Use of the crystalline form (I) of AD-35 according to any one of claims 1 to 3, the crystalline form (II) of AD-35 according to any one of claims 4 to 6, the crystalline form (III) of AD-35 according to any one of claims 7 to 9, the crystalline form (IV) of AD-35 according to any one of claims 10 to 12, the crystalline form (V) of AD-35 according to any one of claims 13 to 15, the crystalline form (VI) of AD-35 according to any one of claims 16 to 18, or the pharmaceutical composition according to claim 25 in the preparation of a medicament for treating Alzheimer's disease.

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