# US 8,541,597 B2 · Process for preparing biphenyl imidazole compounds

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- Number: US 8,541,597 B2
- Document ID: US8541597B2
- Status: Granted
- Kind: B2
- Application number: 13/455,339
- Filed: 2012-04-25
- Published: 2012-08-16
- Granted: 2013-09-24
- Earliest claimed: 2009-09-29
- Assignees: Theravance, Inc.
- Applicants: Weijiang Zhang; Pierre-Jean Colson
- Inventors: Weijiang Zhang; Pierre-Jean Colson
- Web page: https://patentgrep.com/patent/US8541597B2

## CPC

- C07D 233/70: One oxygen atom
- A61P 9/12: Antihypertensives
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 233/68: Halogen atoms
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The invention provides processes for preparing intermediates useful for preparing compounds of the formula: or a salt thereof, where R1-3 are as defined in the specification.

## Claims

### Claim 1

A process for preparing a compound of formula II:
or a salt thereof; where R1 is —C1-6 alkyl; R2 is —O—C1-5alkyl; and P is a carboxylic acid protecting group; the process comprising the steps of:
(a) reacting a compound of formula I:
with a potassium-C1-6alkyl-trifluoroborate reagent in the presence of a palladium-phosphine catalyst to form a compound of formula 3:
(b) reacting the compound of formula 3 with hydroxylamine or a salt thereof to form a compound of formula 4:
and
(c) reacting the compound of formula 4 with a reducing agent to form a compound of formula II or a salt thereof.

### Claim 2 (depends on 1)

The process of claim 1, where the palladium-phosphine catalyst is a combination of a palladium catalyst and a source of phosphine.

### Claim 3 (depends on 2)

The process of claim 2, where the palladium catalyst is palladium(II)acetate and the source of phosphine is di(1-adamantyl)-n-butylphosphine.

### Claim 4 (depends on 1)

The process of claim 1, where the reducing agent is hydrogen/Raney nickel or Pd/C.

### Claim 5 (depends on 1)

The process of claim 1, further comprising the step of preparing a crystalline form of the compound of formula II.