# US 11,028,082 B2 · Process for the preparation of a novel umeclidinium synthesis intermediate

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- Number: US 11,028,082 B2
- Document ID: US11028082B2
- Status: Granted
- Kind: B2
- Application number: 16/617,928
- Filed: 2018-05-28
- Published: 2020-04-02
- Granted: 2021-06-08
- Earliest claimed: 2017-05-30
- Assignees: Olon S.P.A.
- Applicants: Olon S.P.A.
- Inventors: Giorgio Bertolini; Corrado Colli; Filippo Nisic; Mara Sada; Stefania Bertuolo; Silvano Ronzoni; Stefano Maiorana; Romano Di Fabio
- Web page: https://patentgrep.com/patent/US11028082B2

## CPC

- C07D 453/02: containing not further condensed quinuclidine ring systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a process for the preparation of a novel and versatile synthesis intermediate and its use in the preparation of umeclidinium. The invention also relates to some reference standards allowing to detect impurity traces recurring in the preparation of umeclidinium and a process for their preparation.

## Claims

### Claim 1

A Process for the preparation of a compound of formula (I) or one of its salts
which comprises reacting a compound of formula (II)
with a compound selected from phenyl lithium and phenyl magnesium bromide, in a suitable solvent, optionally isolating the so-obtained compound of formula (I) and optionally transforming it into one of its salts.

### Claim 2 (depends on 1)

The process according to claim 1, wherein said solvent is selected from aprotic solvents.

### Claim 3 (depends on 1)

The process according to claim 1, wherein phenyl lithium is used at a rate of 1.2-1.3 moles per mole of compound of formula (II).

### Claim 4 (depends on 1)

The process according to claim 1, wherein said compound of formula (II) is obtained
by reacting a compound of formula (III)
wherein X is a leaving group with a strong base in a suitable solvent, to give the compound of formula II

### Claim 5 (depends on 1)

The process according to claim 1, wherein said compound of formula (II) is obtained
by reacting the Weinreb amide of quinuclidine with phenyl lithium or phenyl magnesium bromide.

### Claim 6 (depends on 1)

The process according to claim 1, wherein said solvent is selected from aprotic solvents and mixtures thereof.

### Claim 7 (depends on 1)

The process according to claim 1, wherein said solvent is selected from the group consisting of ethers, aliphatic hydrocarbons, aromatic hydrocarbons and mixtures thereof.

### Claim 8 (depends on 1)

The process according to claim 1, wherein said solvent is selected from the group consisting of tetrahydrofuran (THF), methyl-tert-butyl ether (MTBE), toluene and mixtures thereof.

### Claim 9 (depends on 1)

The process according to claim 1, comprising reacting said compound of formula (II) with phenyl lithium.

### Claim 10 (depends on 1)

The process according to claim 1, wherein said phenyl lithium is added in stoichiometric amount or in slight excess with respect to the compound of formula (II).

### Claim 11 (depends on 4)

The process according to claim 4, wherein said leaving group is selected from halogen, tosyl, mesyl and triflate.

### Claim 12

A method of preparing the compound of formula (I) and/or umeclidinium using the compound of formula (II) and/or the compound of Formula (III) as intermediates

### Claim 13

A compound of formula (II)
or one of its salts.

### Claim 14 (depends on 13)

The salt of the compound of formula II
according to claim 13, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, sulphate and phosphate.