Methods for the preparation of sphingosine 1-phosphate receptor modulators and solid forme thereof

1 . A Siponimod adipic acid co-crystal, or a solvate or hydrate, and premixes thereof.

2 . The Siponimod adipic acid co-crystal according to claim 1 , wherein the mole ratio of Siponimod to adipic acid is ranging from 1:0.25 to 1:1.2.

3 . The Siponimod adipic acid co-crystal according to claim 1 , wherein the co-crystal has an XRD pattern comprising peaks at 6.50, 16.79, and 21.85±0.2° 2θ.

4 . The Siponimod adipic acid co-crystal according to claim 1 in a crystalline Form.

5 . A process for preparing Siponimod adipic acid co-crystal according to claim 1 , the process comprising:

a) dissolving Siponimod and adipic acid in a first organic solvent at a temperature of 25° C. to a reflux temperature of the first organic solvent;

b) removing the first organic solvent to produce a residue;

c) stirring the residue in a second organic solvent for at least 1 hour to 30 hours at 25-30° C. to produce a precipitate of the Siponimod adipic acid co-crystal;

d) isolating the precipitate of the Siponimod adipic acid co-crystal; and

e) drying the isolated precipitate at 30-60° C. for at least 1 hour to 10 hours.

6 . The process according to claim 5 , wherein the Siponimod is in a polymorphic form or in a mixture of polymorphic forms.

7 . The process according to claim 5 , wherein the first organic solvent is selected from the group comprising of C1 to C5 alcohols; nitriles; C1 to C6 halogenated hydrocarbons; C6 to C14 aromatic hydrocarbons, C2 to C7 esters; C4 to C7 ethers; cyclic ether; aromatic ethers; DMF, DMSO, and mixtures thereof.

8 . The process according to claim 5 , wherein the first organic solvent is selected from the group comprising of methanol, ethanol, isopropanol, t-butanol, acetonitrile, propionitrile, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, ethylbenzene, propylbenzene, butylbenzene, trimethylbenzene, tetramethylbenzene, cyclohexylbenzene, ethyl acetate, methyl acetate, isopropyl acetate, dimethyl ether, diethyl ether, ethyl methyl ether, tetrahydrofuran, 1,4-dioxane, diphenyl ether, DMF, DMSO, and mixtures thereof.

9 . The process according to claim 5 , further comprising:

prior to step (a), preparing the siponimod by

converting a compound of Formula XI:

wherein R1 is a C1-C4 alkyl group, to siponimod.

10 . The process according to claim 9 , wherein converting the compound of Formula XI comprises:

reacting the compound of Formula XI with a compound of Formula IX or a salt thereof:

in the presence of a solvent to provide a compound of Formula X or a salt thereof:

wherein R1 is the C1-C4 alkyl group; and

hydrolyzing the compound of Formula X or the salt thereof in the presence of an acid or a base to provide the Siponimod.

11 . The process according to claim 9 , further comprising preparing the compound of Formula XI by

i) reacting a compound of Formula XIII:

wherein R2 is a leaving group selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, and acetyl, with a compound of Formula XII:

wherein R1 is the C1-C4 alkyl group, in the presence of a first base and a first solvent to provide the compound of Formula XI; or

ii) reacting a compound of Formula VI:

wherein X 2 is a leaving group selected from the group consisting of chloro, bromo, and iodo, with the compound of Formula XII in the presence of a second base and a second solvent, to provide the compound of Formula XI.

12 . The process according to claim 10 , wherein the compound of Formula IX or the salt thereof is prepared by reacting a compound of Formula II:

wherein X 1 is a leaving group selected from the group consisting of bromo, chloro, iodo, and fluoro, with n-hydroxy phthalimide of Formula XV

in the presence of a second base and a second solvent to provide a compound of Formula XIV

reacting the compound of Formula XIV with hydrazine or a salt thereof in the presence of a third solvent to provide the compound of Formula IX; and optionally

converting the compound of Formula IX to the salt thereof.

13 . A pharmaceutical composition, comprising the Siponimod adipic acid co-crystal according to claim 1 , and one or more pharmaceutically acceptable excipients.

14 . A method of treating a relapsing form of multiple sclerosis in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of the Siponimod adipic acid co-crystal according to claim 1 .