# US 10,865,187 B2 · Methods for the synthesis of deuterated dextromethorphan

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- Number: US 10,865,187 B2
- Document ID: US10865187B2
- Status: Granted
- Kind: B2
- Application number: 16/910,353
- Filed: 2020-06-24
- Published: 2020-10-08
- Granted: 2020-12-15
- Earliest claimed: 2016-07-04
- Assignees: Avanir Pharmaceuticals
- Applicants: Avanir Pharmaceuticals, Inc.
- Inventors: Matt Johnson; Cunxiang Zhao; Weihua Meng; Zhijun Lu; Yan Li
- Web page: https://patentgrep.com/patent/US10865187B2

## CPC

- C07D 221/28: Morphinans
- C07D 471/08: Bridged systems
- C07B 59/002: {Heterocyclic compounds}
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The application describes methods for making a deuterated dextromethorphan of Formula (I), deuterated dextromethorphan produced by these methods, and pharmaceutically acceptable salts thereof.

## Claims

### Claim 1

A method for synthesizing a deuterated dextromethorphan of Formula (I) or a pharmaceutically acceptable salt thereof
the method comprising:
(i) N-demethylating the tertiary amine of a dextromethorphan compound of Formula (II)
to form an N-demethylated compound of Formula (V)
(ii) deuterating the N-demethylated compound of Formula (V) to a compound of Formula (III)
by N-methylation in the presence of a base and iodomethane-D3 at a temperature in the range of −90° C. to 90° C. inclusive;
(iii) O-demethylating the methoxy group of Formula (III) to a compound of Formula (VI)
and
(iv) deuterating the O-demethylated compound of Formula (VI) to the compound of Formula (I) by O-methylation in the presence of a base and iodomethane-D3 at temperatures in the range of −10° C. to 10° C. inclusive.

### Claim 2 (depends on 1)

The method of claim 1, wherein the N-demethylation of step (i) is conducted in the presence of 1-chloroethyl chloroformate.

### Claim 3 (depends on 1)

The method of claim 1, wherein the O-demethylation of step (iii) is conducted in the presence of hydrobromic acid.

### Claim 4 (depends on 1)

The method of claim 1, wherein the base used in step (ii) is chosen from sodium carbonate, cesium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride, n-butyllithium, lithium diisopropylamide, and a tertiary organic amine.

### Claim 5 (depends on 1)

The method of claim 1, further comprising converting the compound of Formula (I) to a hydrobromide monohydrate salt of Formula (IV)
by crystallization using a solution comprising hydrobromic acid.

### Claim 6 (depends on 1)

The method of claim 1, wherein the base used in step (ii) is n-butyllithium.