Process for making modulators of cystic fibrosis transmembrane conductance regulator

A process for the preparation of a compound of Formula 1,

• comprising coupling a carboxylic acid of Formula 2
• with an aniline of Formula 3
• in the presence of a coupling agent selected from the group consisting of 2-chloro-1,3-dimethyl-2-imidazolium tetrafluoroborate, HBTU, HCTU, 2-chloro-4,6-dimethoxy-1,3,5-triazine, HATU, HOBT/EDC, and propane phosphonic anhydride;
• wherein
• each R2 and R4 is independently selected from hydrogen, CN, CF3, halo, C1-6 straight or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-10 heteroaryl or C3-7 heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, and each C1-6 straight or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-10 heteroaryl or C3-7 heterocyclic is independently and optionally substituted with up to three substituents selected from —OR′, —CF3, —OCF3, SR′, S(O)R′, SO2R′, —SCF3, halo, CN, —COOR′, —COR′—, —O(CH2)2N(R′)(R′), —O(CH2)N(R′)(R′), —CON(R′)(R′), —(CH2)2OR′, —(CH2)OR′, CH2CN, optionally substituted phenyl or phenoxy, —N(R′)(R′), —NR′C(O)OR′, —NR′C(O)R′, —(CH2)2N(R′)(R′), or —(CH2)N(R′)(R′);
• R5 is —OC(O)OR′, —OC(O)NHR′, —OC(O)N(R′)2, wherein R′ is not hydrogen, or
• R4 and R5 are taken together form the moiety,
• each X is independently a bond or is an optionally substituted C1-6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—;
• each Rx is independently R′, halo, NO2, CN, CF3, or OCF3;
• y is an integer from 0-4;
• and
• each R′ is independently selected from hydrogen or an optionally substituted group selected from a C1-8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from N, O, or S.