Process of making 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof

Patent metadata

Field	Value
Publication number	US-11905232-B2
Application number	US-202017429183-A
Country	US
Kind code	B2
Filing date	Feb 10, 2020
Priority date	Feb 8, 2019
Publication date	Feb 20, 2024
Grant date	Feb 20, 2024

Abstract

The disclosure provides a process for the preparation of 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof, contemplated to be capable of modulating the activity of receptors, e.g., PPARs receptors.

First claim

What is claimed is:

1. A process for preparing a substantially optically pure compound of Formula (VII):

the process comprising:
reacting a compound of Formula (I):

 with an activating agent, in the optional presence of a base, to form an intermediate of Formula (I-A):

 wherein LG is a leaving group;
treating the intermediate of Formula (I-A) with a base solution in the presence of an alcohol solvent, to eliminate the leaving group and thereby forming an intermediate of Formula (I-B):

hydrolyzing the intermediate of Formula (I-B) to form a compound of Formula (IV):

hydrogenating the compound of Formula (IV) to form a compound of Formula (V):

resolving the compound of Formula (V) to form a substantially optically pure compound of Formula (VI):

 and
acylating the compound of Formula (VI) to form the compound of Formula (VII).

2. The process of claim 1 , wherein reacting a compound of Formula (I) with an activating agent comprises reacting in the presence of the base and a solvent.

3. The process of claim 2 , wherein the solvent in the reacting step is selected from the group consisting of toluene, dichloromethane, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, and acetonitrile.

4. The process of claim 1 , wherein the base in the reacting step is an amine base.

5. The process of claim 1 , wherein the activating agent is methanesulfonyl chloride.

6. The process of claim 1 , wherein the leaving group is —OSO 2 Me.

7. The process of claim 1 , wherein the alcohol solvent comprises methanol.

8. The process of claim 1 , wherein the base solution comprises sodium hydroxide.

9. The process of claim 1 , wherein hydrolyzing the intermediate of Formula (I-B) to form a compound of Formula (IV) comprises:
(i) contacting the intermediate of Formula (I-B) with an alkali hydroxide and water; and
neutralizing to form the compound of Formula (IV).

10. The process of claim 9 , wherein neutralizing comprises acidifying to a pH of less than or equal to 3 with an acid.

11. The process of claim 1 , wherein hydrogenating the compound of Formula (IV) to form a compound of Formula (V) comprises contacting the compound of Formula (IV) with hydrogen and a catalyst.

12. The process of claim 1 , wherein resolving the compound of Formula (V) to form a substantially optically pure compound of Formula (VI) comprises:
(a) resolving a compound of Formula (V) in the presence of a chiral acid thereby forming a chiral salt of the compound of Formula (VI); and
(b) neutralizing the chiral salt of the compound of Formula (VI) thereby forming the compound of Formula (VI).

13. The process of claim 12 , wherein the chiral salt of the compound of Formula (VI) is:

14. The process of claim 12 , wherein neutralizing comprises contacting the chiral salt of the compound of Formula (VI), with (i) an aqueous base; and then (ii) acidifying the solution by adding an acid.

15. The process of claim 1 , wherein acylating comprises contacting the compound of Formula (VI) with acetic anhydride in the presence of an organic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane, and toluene.

16. The process of claim 1 , wherein the substantially optically pure compound of Formula (VII) is at least 98% of the enantiomer:

expressed as a percentage of both enantiomers.

17. A process for preparing a compound of Formula (I):

the process comprising, providing a mixture of a compound of Formula (II):

and a compound of Formula (III):

and contacting the mixture with a base; thereby forming a compound of Formula (I).

18. The process of claim 17 , wherein contacting occurs in tetrahydrofuran.

19. A compound represented by:

or a pharmaceutically acceptable salt thereof.

Assignees

• Nogra Pharma Ltd

Inventors

• Demartis Salvatore
• Viti Francesca
• Mcnulty Marie

Classifications

• C07B2200/07

  Optical isomers · CPC title

• A61K31/195

  having an amino group · CPC title

• C07C227/16

  by reactions not involving the amino or carboxyl groups · CPC title

• C07C303/28

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

• C07C201/12

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