# US 10,479,766 B2 · Deuterated CFTR potentiators

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- Number: US 10,479,766 B2
- Document ID: US10479766B2
- Status: Granted
- Kind: B2
- Application number: 16/033,802
- Filed: 2018-07-12
- Published: 2019-06-06
- Granted: 2019-11-19
- Earliest claimed: 2011-05-18
- Assignees: Verex Pharmaceuticals (Europe) Limited
- Applicants: Vertex Pharmaceuticals (Europe) Limited
- Inventors: Adam J. Morgan
- Web page: https://patentgrep.com/patent/US10479766B2

## CPC

- C07D 215/56: with oxygen atoms in position 4
- C07B 59/002: {Heterocyclic compounds}
- 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)

## Abstract

This invention relates to compounds of Formula I: and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a CFTR potentiator.

## Claims

### Claim 1

A process for preparing Compound 106
or a pharmaceutically acceptable salt thereof, comprising reacting Compound 12
with Compound 6
wherein any atom not designated as deuterium is present at its natural isotopic abundance, wherein the percentage of isotopic enrichment for each designated deuterium is at least 90%, and
optionally treating Compound 106 with a base to produce a pharmaceutically acceptable salt of Compound 106.

### Claim 2 (depends on 1)

The process of claim 1, wherein the reaction of Compound 12 with Compound 6 is performed in the presence of a coupling agent and base.

### Claim 3 (depends on 2)

The process of claim 2, wherein the coupling agent is (N,N,N′,N′)-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate and the base is N,N′-diisopropylethylamine.

### Claim 4 (depends on 1)

The process of claim 1, wherein Compound 12 is produced by converting Compound 10
into Compound 12

### Claim 5 (depends on 4)

The process of claim 4, wherein Compound 10 is converted to Compound 12 with a reducing agent.

### Claim 6 (depends on 5)

The process of claim 5, wherein the reducing agent is an acid.

### Claim 7 (depends on 6)

The process of claim 6, wherein the acid is HCl.

### Claim 8 (depends on 1)

The process of claim 1, wherein Compound 9
is converted into Compound 10

### Claim 9 (depends on 8)

The process of claim 8, wherein Compound 9 is converted to Compound 10 in the presence of a reducing agent and metal catalyst.

### Claim 10 (depends on 9)

The process of claim 9, wherein the reducing agent is ammonium formate and the metal catalyst is palladium on carbon.

### Claim 11 (depends on 1)

The process of claim 1, wherein Compound 9 is produced by converting Compound 8
into Compound 9

### Claim 12 (depends on 11)

The process of claim 11, wherein Compound 8 is reacted with HNO3/H2SO4 to form a nitrated product.

### Claim 13 (depends on 12)

The process of claim 12, wherein the nitration product is subjected to potassium hydroxide in methanol to form Compound 9.

### Claim 14 (depends on 1)

The process of claim 1, wherein Compound 8 is produced by converting Compound 7
into Compound 8

### Claim 15 (depends on 14)

The process of claim 14, wherein the conversion of Compound 7 into Compound 8 is performed in the presence of an acyloxycarbonylating agent and base.

### Claim 16 (depends on 15)

The process of claim 15, wherein the acyloxycarbonylating agent is methyl chloroformate and the base is triethylamine.

### Claim 17 (depends on 14)

The process of claim 14, wherein the conversion of Compound 7 into Compound 8 is performed in the presence of 4-dimethylaminopyridine.

### Claim 18 (depends on 1)

The process of claim 1, wherein the process further comprises converting tert-butyl phenol
into Compound 7

### Claim 19 (depends on 18)

The process of claim 18, wherein the conversion of tert-butyl phenol into Compound 7 is performed in the presence of a source of X—C(CD3)3 and an acid.

### Claim 20 (depends on 19)

The process of claim 19, wherein the source of X—C(CD3)3 is tert-butanol-d10 and the acid is D2SO4.