IP Library › Granted Patent US 12,247,012
Granted Patent B2
US 12,247,012 · App. 17/937,283 · Granted Mar 11, 2025

Synthesis of nirogacestat

Inventors: Kristin Patterson (Stamford, CT); Mark Hatcher (Stamford, CT)
Assignee: SPRINGWORKS THERAPEUTICS, INC.
C07D233/88C07C227/26C07D263/44
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Quick Facts
Patent No.
US 12,247,012
App. No.
17/937,283
Granted
Mar 11, 2025
Kind
B2
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”).

Claims (25)

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.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 21, 2024
From: PATTERSON, KRISTIN; HATCHER, MARK
To: SPRINGWORKS THERAPEUTICS, INC.
Reel/Frame 069362/0438 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2022
From: PATTERSON, KRISTIN; HATCHER, MARK
To: SPRINGWORKS THERAPEUTICS, INC.
Reel/Frame 061494/0930 →
Continuity (3)
Continuation 17929153 · Sep 1, 2022
Provisional Application 63239696 · Sep 1, 2021
Related Publication 20230091415A1 · Mar 23, 2023
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