Addition salt of S1P1 receptor agonist and crystal form thereof, and pharmaceutical composition

1. A maleate of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid, having a structure represented by the following formula:

2. The maleate according to claim 1 , wherein the maleate is substantially a crystal form, wherein with Cu-Kα radiation, the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions: 10.6±0.2°, 16.3±0.2°, 19.5±0.2°, 21.5±0.2°, and 26.9±0.2°.

3. The maleate according to claim 2 , wherein the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions: 7.0±0.2°, 10.6±0.2°, 13.6±0.2°, 16.3±0.2°, 19.5±0.2°, 20.1±0.2°, 21.5±0.2°, 24.5±0.2°, and 26.9±0.2°.

4. The maleate according to claim 2 , wherein the crystal form has a Fourier transform infrared spectrum having characteristic peaks at wavenumbers 1734 cm −1 , 1574 cm −1 , 1485 cm −1 , 1439 cm −1 , 1364 cm −1 , 1346 cm −1 , 1080 cm −1 , 1003 cm −1 , 893 cm −1 , 871 cm −1 , 757 cm −1 , and 729 cm −1 .

5. A method for preparing the maleate according to claim 1 , comprising the following steps:

forming a suspension or solution of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid in a solvent selected from the group consisting of a C 1 -C 4 alcohol, a C 3 -C 4 ketone, C 4 -C 6 ether, a C 2 -C 5 ester, and water, and mixtures thereof and a suspension or solution of maleic acid in a solvent selected from the group consisting of a C 1 -C 4 alcohol, a C 3 -C 4 ketone, C 4 -C 6 ether, a C 2 -C 5 ester, and water, and mixtures thereof;

mixing the suspension or solution of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid and the suspension or solution of maleic acid in a molar ratio of 1:1 to 1:5 of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid to maleic acid for reaction;

removing the solvent after the reaction is complete; and

performing drying.

6. The maleate according to claim 2 , wherein the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions with relative intensities as follows:

2θ

Relative intensity %

 5.3 ± 0.2°

3.4

 7.0 ± 0.2°

5.8

10.6 ± 0.2°

100

13.6 ± 0.2°

6.6

14.5 ± 0.2°

3.2

16.3 ± 0.2°

12.2

19.5 ± 0.2°

37.7

20.1 ± 0.2°

8.6

20.7 ± 0.2°

2.8

21.5 ± 0.2°

18.3

24.5 ± 0.2°

11.4

24.7 ± 0.2°

9.6

25.3 ± 0.2°

1.8

26.1 ± 0.2°

1.9

26.9 ± 0.2°

34.5

28.7 ± 0.2°

2.2.

7. The maleate according to claim 2 , wherein the crystal form has an X-ray powder diffraction pattern substantially as illustrated in FIG. 10 .

8. The maleate according to claim 1 , wherein the maleate is an anhydrate, a hydrate, or a non-solvate.

9. The method according to claim 5 , wherein the solvent is selected from the group consisting of ethanol, acetone, ether, water, ethyl acetate, and 1,4-dioxane, and mixtures thereof.

10. The method according to claim 5 , wherein the molar ratio of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid to maleic acid is 1:1.0 to 1:2.6.

11. The method according to claim 5 , wherein the reaction is performed at 10° C. to 60° C.

12. The method according to claim 5 , wherein the reaction is performed under stirring.

13. The method according to claim 5 , wherein the drying is performed at a temperature of 10° C. to 60° C.

14. The method according to claim 5 , wherein the ratio of mass of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid to volume of the solvent in the method is 1 mg:1 mL to 50 mg:1 mL.