# US 11,993,608 B2 · Selective estrogen receptor degraders

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,993,608 B2
- Document ID: US11993608B2
- Status: Granted
- Kind: B2
- Application number: 18/121,667
- Filed: 2023-03-15
- Published: 2023-07-27
- Granted: 2024-05-28
- Earliest claimed: 2018-07-12
- Assignees: Eli Lilly and Company
- Applicants: Eli Lilly and Company
- Inventors: Jolie Anne Bastian; Jeffrey Daniel Cohen; Almudena Rubio; Daniel Jon Sall; Jennifer Anne Mcmahon
- Web page: https://patentgrep.com/patent/US11993608B2

## CPC

- C07D 491/052: the oxygen-containing ring being six-membered
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Novel selective estrogen receptor degraders (SERDs) according to the formula: pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, wherein either R1 or R2 is independently selected from Cl, F, —CF3, or —CH3, and the other is hydrogen, and methods for their use are provided.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

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

### Claim 4 (depends on 3)

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).

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 4)

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.

### Claim 7 (depends on 6)

The process according to claim 6, wherein
is prepared by treating
with boron tribromide in a solvent, wherein the solvent comprises dichloromethane.

### Claim 8 (depends on 6)

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.

### Claim 9 (depends on 2)

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/CO2, and wherein enantioenriched isomer 1 is the first isomer to elute from the Chiralpak AD-H column.

### Claim 10 (depends on 2)

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 CO2, wherein isomer 1 is the first enantiomer to elute from the LUX® Cellulose column.

### Claim 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.

### Claim 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.