Selective estrogen receptor degraders

Patent metadata

Field	Value
Publication number	US-11993608-B2
Application number	US-202318121667-A
Country	US
Kind code	B2
Filing date	Mar 15, 2023
Priority date	Jul 12, 2018
Publication date	May 28, 2024
Grant date	May 28, 2024

Abstract

Novel selective estrogen receptor degraders (SERDs) according to the formula:

pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein either R 1 or R 2 is independently selected from Cl, F, —CF 3 , or —CH 3 , and the other is hydrogen, and methods for their use are provided.

First claim

What is claimed is:

1. A process for preparing a compound of the formula

the process comprising:
treating a racemic compound of the formula

 with a base, in a solvent, wherein the base comprises sodium hydride and the solvent comprises tetrahydrofuran.

2. The process according to claim 1 , wherein the racemic compound

is prepared by treating

with a reducing agent in a solvent, wherein the reducing agent comprises lithium triethylborohydride and the solvent comprises 1,4-dioxane, tetrahydrofuran or both 1,4-dioxane and tetrahydrofuran.

3. The process according to claim 2 , wherein the lithium triethylborohydride is dissolved in tetrahydrofuran.

4. The process according to claim 3 , wherein the compound of the formula

is prepared by treating a compound of the formula

with 2-fluoro-4-(trifluoromethyl)phenylboronic acid, a base comprising potassium carbonate, a solvent comprising 2-methyl-2-butanol and water, and a palladium catalyst comprising chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).

5. The process according to claim 4 , wherein the process is performed in a sealed container that is microwaved.

6. The process according to claim 4 , wherein

is prepared by treating

With 2-[3-(fluoromethyl)azetidin-1-yl]ethan-1-ol hydrochloride, a base comprising sodium hydride and a solvent comprising dimethylformamide.

7. The process according to claim 6 , wherein

is prepared by treating

with boron tribromide in a solvent, wherein the solvent comprises dichloromethane.

8. The process according to claim 6 , wherein

is prepared by treating 4-bromo-3-chloro-7-methoxyquinoline with isopropylmagnesium chloride and 4-fluorobenzoyl chloride in a solvent comprising tetrahydrofuran.

9. The process according to claim 2 , wherein the racemic compound of the formula

is purified using chiral chromatography to afford enantioenriched isomer 1, wherein the chiral chromatography comprises a Chiralpak AD-H column and a mobile phase comprising 35% iPrOH with 0.5% DMEA/CO 2 , and wherein enantioenriched isomer 1 is the first isomer to elute from the Chiralpak AD-H column.

10. The process according to claim 2 , wherein the racemic compound of the formula

is purified using chiral chromatography to afford enantioenriched isomer 1, wherein the chiral chromatography comprises a LUX® Cellulose-1, 5×25 cm; eluting with a mobile phase of 30% iPrOH (with 0.5% DMFA) in CO 2 , wherein isomer 1 is the first enantiomer to elute from the LUX® Cellulose column.

11. A process for preparing (4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl){3-[2-fluoro-4-(trifluoromethyl)phenyl]-7-hydroxyquinolin-4-yl}methanone Isomer 1, the process comprising reducing

with a chiral reducing agent in a solvent, wherein the chiral reducing agent is made by treating (R)-(+)-α.α-diphenyl-2-pyrrolidinemethanol with trimethylborate and the solvent is tetrahydrofuran.

12. A process for preparing enantioenriched, isomer 1 of compound of the formula

the process comprising treating (4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl)(hydroxy)methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinolin-7-ol, isomer 1, with a base in a solvent, wherein the base comprises cesium carbonate and the solvent comprises dimethylsulfoxide.

Assignees

• Lilly Co Eli

Inventors

• Bastian Jolie Anne
• Cohen Jeffrey Daniel
• Rubio Almudena
• Sall Daniel Jon
• McMahon Jennifer Anne

Classifications

• C07D491/052 Primary

  the oxygen-containing ring being six-membered · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title