Processes for making modulators of cystic fibrosis transmembrane conductance regulator
The disclosure provides processes for synthesizing compounds for use as CFTR modulators.
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.