Development of an Enantioselective [3 + 2] Cycloaddition To Synthesize the Pyrrolidine Core of ABBV-3221 on Multikilogram Scale

Abstract

The tetrasubstituted pyrrolidine core of ABBV-3221 was synthesized by catalytic, enantioselective cycloaddition. A Cu­(I) catalyst system was identified as ideal for further development, which gave a 78% yield of 99% purity product after optimization. The processes of catalyst selection, optimization, and crystallization of the cycloaddition product are described herein.

Preclinical Studies of a Rare CF-Causing Mutation in the Second Nucleotide Binding Domain (c.3700A>G) Show Robust Functional Rescue in Primary Nasal Cultures by Novel CFTR Modulators

“…Corrector AC2-1 (X281632) belongs to the ABBV/GLPG2737 series type C2 correctors belonging to the pyrazolopyridine acylsulphonamide chemical class correctors and is a close analog of compound 93 described in the review by Kym et al [ 28 ] and covered in the patent granted to Galapagos and Abbvie (Patent WO2017060874A1; 2017). Corrector AC2-2 (X300549) belongs to the ABBV/GLPG3221 series type C2 correctors belonging to the pyrrolidine chemical class of correctors and is described as Compound 4 in an Abbvie manuscript [ 29 ] and is a close analog of ABBV/GLPG3221 [ 30 ]. Potentiator AP2 (X300529) belongs to the sulphonamide-substituted aminopyridines class of potentiators and is a close analog of GLPG2451 [ 31 ] and compound 48 described in the review by Kym et al and covered in a patent granted to Galapagos and Abbvie (Patent WO2016193812A1, 2016).…”

Organic Superbases in Recent Synthetic Methodology Research

“…alkenes and nitroarenes). A useful application of this reaction is the sequential 1,3‐dipolar cycloaddition/Nef reaction to access stereopure 3‐pyrrolidinones, precursors to bioactive 3‐hydroxypyridines [52] …”

Functional rescue of c.3846G>A (W1282X) in patient-derived nasal cultures achieved by inhibition of nonsense mediated decay and protein modulators with complementary mechanisms of action

“…Corrector AC2-1 (X281632) belongs to the ABBV/GLPG2737 series type C2 correctors belonging to the pyrazolopyridine acylsulphonamide chemical class correctors and is a close analog of compound 93 described in the review by Kym et al [44] and covered in the patent granted to Galapagos and Abbvie (Patent WO2017060874A1; 2017). Corrector AC2-2 (X300549) belongs to the ABBV/GLPG3221 series type C2 correctors belonging to the pyrrolidine chemical class of correctors and is described as Compound 4 in an Abbvie manuscript [45] and is a close analog of ABBV/GLPG3221 [46] . Potentiator AP2 (X300529) belongs to the sulphonamide-substituted aminopyridines class of potentiators and is a close analog of GLPG2451 [47] and compound 48 described in the review by Kym et al and covered in a patent granted to Galapagos and Abbvie (Patent WO2016193812A1, 2016).…”