Processes for making modulators of cystic fibrosis transmembrane conductance regulator

Patent metadata

Field	Value
Publication number	US-11708331-B2
Application number	US-201816768178-A
Country	US
Kind code	B2
Filing date	Nov 30, 2018
Priority date	Dec 1, 2017
Publication date	Jul 25, 2023
Grant date	Jul 25, 2023

Abstract

The disclosure provides processes for synthesizing compounds for use as CFTR modulators.

First claim

The invention claimed is:

1. A compound selected from:

and salts thereof.

2. A process for the preparation of compound 1:

comprising:
a) converting compound 12:
into compound 11A:

wherein the conversion of compound 12 into compound 11A is performed in the presence of KNO 3 and/or NaNO 3 , AlCl 3 , and optionally one or more of trimethylsilyl chloride and TiCl 4 ;
b) converting compound 11A into compound 4:

c) reacting compound 3:

with compound 4 to produce compound 5:

and
d) converting compound 5 into compound 1;
wherein the methyl (Me) of the —OCO 2 Me of each of compounds 4, 5, 11A, and 12 is optionally replaced by a group selected from aliphatic, heteroaliphatic, heterocyclic, haloaliphatic, aryl, and heteroaryl.

3. A process for the preparation of compound 11A:

comprising converting compound 12:

into compound 11A;
wherein the conversion of compound 12 into compound 11A is performed in the presence of KNO 3 and/or NaNO 3 , AlCl 3 , and optionally one or more of trimethylsilyl chloride and TiCl 4 ; and
wherein the methyl (Me) of the —OCO 2 Me of each of compounds 11A and 12 is optionally replaced by a group selected from aliphatic, heteroaliphatic, heterocyclic, haloaliphatic, aryl, and heteroaryl.

4. The process of claim 2 or 3 , wherein the conversion of compound 12 into compound 11A is performed in the presence of KNO 3 , AlCl 3 , and trimethylsilyl chloride.

5. The process of claim 2 or 3 , wherein the conversion of compound 12 into compound 11A is performed in the presence of KNO 3 and AlCl 3 .

6. The process of claim 2 or 3 , wherein the conversion of compound 12 into compound 11A is performed in the presence of NaNO 3 and AlCl 3 .

7. The process of claim 2 or 3 , wherein the conversion of compound 12 into compound 11A is performed in the presence of a solvent.

8. The process of claim 7 , wherein the solvent is CH 2 Cl 2 .

9. The process of claim 2 or 3 , wherein compound 12 is produced by converting compound 13:

into compound 12.

Assignees

• Vertex Pharma

Inventors

• Lemercier Lewandowski Berenice
• Lewis Robert
• Looker Adam
• Morgan Adam
• Roeper Stefanie
• Ryan Michael
• Solsona Rocabert Juan Gabriel
• Wilde Nathan

Classifications

• C07D215/56 Primary

  with oxygen atoms in position 4 · CPC title

• C07C201/08 Primary

  by substitution of hydrogen atoms by nitro groups · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07C39/27

  all halogen atoms being bound to ring carbon atoms · CPC title

• C07C69/96

  Esters of carbonic or haloformic acids · CPC title