Synthesis of nirogacestat

Patent metadata

Field	Value
Publication number	US-12247012-B2
Application number	US-202217937283-A
Country	US
Kind code	B2
Filing date	Sep 30, 2022
Priority date	Sep 1, 2021
Publication date	Mar 11, 2025
Grant date	Mar 11, 2025

Abstract

The present disclosures are directed to processes for synthesizing (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide (“nirogacestat”).

First claim

What is claimed is:

1. A process for preparing a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof which is susceptible to oxidation that is substantially free of Compound 13

comprising the steps of:
i) dissolving Compound 11 in a solvent,

ii) reacting Compound 9

with 1,1′-carbonyldiimidazole to form Compound 10,

and iii) combining Compound 10 with Compound 11 to form a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, where Compound 1 has the formula

2. The process of claim 1 , wherein the solvent is an alcohol of the formula R—OH, wherein R is an alkyl, with the proviso that R is not ethyl.

3. The process of claim 1 , wherein the solvent is a primary alcohol, other than ethanol.

4. The process of claim 1 , wherein the solvent is a secondary alcohol.

5. The process of claim 1 , wherein the solvent is a tertiary alcohol.

6. The process of claim 1 , wherein the solvent is 2-methylpropan-1-ol.

7. The process of claim 1 , wherein the solvent is propanol.

8. The process of claim 1 , wherein the solvent is isopropanol.

9. The process of claim 1 , wherein the process further comprises treating Compound 1 with hydrobromic acid.

10. The process of claim 1 , wherein the mixture is maintained at a pH less than 6.

11. The process of claim 1 , wherein the mixture is maintained at a pH less than 3.

12. A pharmaceutical composition comprising Compound 1 prepared by the process of claim 1 , wherein
(a) the composition is substantially free of Compound 13

(b) the composition comprises Compound 2

or a pharmaceutically acceptable salt thereof.

13. The process of claim 9 , wherein the mixture is warmed to 0-5° C. during hydrobromic acid treatment.

14. The process of claim 1 , wherein the process further comprises reacting Compound 1 with an aqueous inorganic acid to form a pharmaceutically acceptable salt of Compound 1.

15. The pharmaceutical composition of claim 12 , wherein the composition comprises:
(1) 98.0% to 99.9% of Compound 1 or a pharmaceutically acceptable salt thereof; and
(2) 0.6% to 0.01% of Compound 2 or a pharmaceutically acceptable salt thereof.

Assignees

• Springworks Therapeutics Inc

Inventors

• Patterson Kristin
• Hatcher Mark

Classifications

• C07D263/44 Primary

  Two oxygen atoms · CPC title

• C07C227/26

  from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles · CPC title

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07B2200/07

  Optical isomers · CPC title

• A61K31/417

  Imidazole-alkylamines, e.g. histamine, phentolamine · CPC title