Process for making Siponimod and intermediate thereof

Patent metadata

Field	Value
Publication number	US-12410126-B2
Application number	US-202017599868-A
Country	US
Kind code	B2
Filing date	Mar 29, 2020
Priority date	Mar 29, 2019
Publication date	Sep 9, 2025
Grant date	Sep 9, 2025

Abstract

The presented invention relates to a process for preparation of compound of formula (I) or a salt or a solvate thereof (i.e.) siponimod. The invention also relates to intermediates used in the process and solid forms of these intermediates.

First claim

The invention claimed is:

1. A process for preparation of Siponimod of formula (I):

or a salt thereof or a solvate thereof, the process comprising:
a) Reacting compound of formula (II) with a compound of formula (III),

wherein LG is a leaving group, R 1 is OH or OProt, and Prot is hydroxyl protective group,
to obtain compound of formula (IV),

wherein R 1 is OH or OProt, and Prot is hydroxyl protective group;
b) Transforming the compound of formula (IV) into Siponimod or a salt thereof or a solvate thereof.

2. The process according to claim 1 wherein LG is a leaving group selected from Cl or Br or I or C 1 -C 10 alkyl or an aryl sulfonate or a perfluoroalkylsulfonate.

3. The process according to claim 1 wherein the compound of formula (II) is compound of formula (IIb),

4. The process according to claim 1 wherein the reaction step a) is performed in a solvent selected from N,N-dimethylformamide or a poorly nucleophilic alcohol or 2-methyl-tetrahydrofurane or acetonitrile or dimethylacetamide or a mixture thereof.

5. The process according to claim 4 wherein the reaction step a) is performed in a mixture N,N-dimethylformamide and butan-2-ol.

6. The process according to claim 1 wherein the step a) is performed in a presence of a base.

7. The process according to claim 1 , wherein R 1 in the compound of formula (III) is OH and the compound of formula (IV) is a compound of formula (IVa):

which further comprises:
reacting the compound of formula (IVa) with an oxidating agent to obtain a compound of formula (VII);

and
reacting the compound of formula (VII) with a compound of formula (VIII) in a presence of a reducing agent in a solvent to obtain the compound of formula (I),

8. The process according to claim 7 wherein the oxidating agent is oxygen.

9. The process according to claim 7 wherein the reducing agent is triethylamine-BH 3 (Et 3 N—BH 3 ) complex.

10. The process according to claim 8 wherein the reducing agent is triethylamine-BH 3 (Et 3 N—BH 3 ) complex.

11. The process according to claim 3 , wherein the reaction step a) is performed in a mixture N,N-dimethylformamide and butan-2-ol.

12. The process according to claim 11 wherein the step a) is performed in a presence of a base.

13. The process according to claim 3 wherein the step a) is performed in a presence of a base.

14. The process according to claim 4 wherein the step a) is performed in a presence of a base.

15. The process according to claim 5 wherein the step a) is performed in a presence of a base.

Assignees

• Synthon Bv

Inventors

• Keltjens Rolf
• Hylse Ondrej
• Partl Jiri

Classifications

• C07C303/28

  by reaction of hydroxy compounds with sulfonic acids or derivatives thereof · CPC title

• C07C249/12

  by reactions not involving the formation of oxyimino groups · CPC title

• C07C249/08

  by reaction of hydroxylamines with carbonyl compounds · CPC title

• C07C17/16

  of hydroxyl groups · CPC title

• C07C251/48

  with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring · CPC title