Iridium(III)-Catalyzed Regioselective C7-Amination of <i>N</i>‑Pivaloylindoles with Sulfonoazides

Direct C7-amination of <i>N</i>-pivaloylindoles has been achieved using a combination of [Cp*IrCl₂]₂, AgNTf₂, and AgOAc as the catalyst and sulfonoazides as the nitrogen source. The reaction proceeded at room temperature to 80 °C to afford 7-sulfonamidoindoles in good to excellent yields. The reaction is broadly applicable to the C7-amination of a wide variety of 3-, 4-, 5-, and 6-substituted <i>N</i>-pivaloylindoles with either alkyl or aryl sulfonoazides

Iridium(III)-Catalyzed Regioselective C7-Amination of <i>N</i>‑Pivaloylindoles with Sulfonoazides

Direct C7-amination of <i>N</i>-pivaloylindoles has been achieved using a combination of [Cp*IrCl₂]₂, AgNTf₂, and AgOAc as the catalyst and sulfonoazides as the nitrogen source. The reaction proceeded at room temperature to 80 °C to afford 7-sulfonamidoindoles in good to excellent yields. The reaction is broadly applicable to the C7-amination of a wide variety of 3-, 4-, 5-, and 6-substituted <i>N</i>-pivaloylindoles with either alkyl or aryl sulfonoazides

Concise Cu (I) Catalyzed Synthesis of Substituted Benzofurans via a Tandem SNAr/C–O Coupling Process

A novel and convergent approach to tetrasubstituted benzofurans was developed from <i>ortho</i>-bromo aryl fluorides and keto-amides via one-pot SNAr displacement and subsequent Cu­(I) catalyzed C–O coupling on the <i>ortho</i>-bromide. The scope of this methodology was demonstrated on several similar substrates

Promotion of a Ti-Mediated Mannich Reaction by a Proton Source

Low temperature NMR studies revealed that a diastereoselective Mannich reaction between a phenyl oxazolidone-derived titanium enolate and an aromatic aldimine was found to occur only after introduction of a proton source. While various protic additives could be used to promote the transformation, the best results were obtained using AcOH to afford the corresponding Mannich products in high diastereoselectivities and yields

Promotion of a Ti-Mediated Mannich Reaction by a Proton Source

Low temperature NMR studies revealed that a diastereoselective Mannich reaction between a phenyl oxazolidone-derived titanium enolate and an aromatic aldimine was found to occur only after introduction of a proton source. While various protic additives could be used to promote the transformation, the best results were obtained using AcOH to afford the corresponding Mannich products in high diastereoselectivities and yields

A Robust Kilo-Scale Synthesis of Doravirine

Doravirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kilo-scale synthesis for its manufacture. The structure and origin of major impurities were determined and their downstream fate-and-purge studied. This resulted in a redesign of the route to introduce the key nitrile functionality via a copper mediated cyanation which allowed all impurities to be controlled to an acceptable level. The improved synthesis was scaled to prepare ∼100 kg batches of doravirine to supply all preclinical and clinical studies up to phase III. The synthesis affords high-quality material in a longest linear sequence of six steps and 37% overall yield

Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer’s Disease

Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer’s disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The second-generation route replaces this with a copper-catalyzed C–N coupling, allowing for more direct access to the target. Other features of the new route include a diastereoselective Mannich-type addition into an Ellman sulfinyl ketimine and a late-stage guanidinylation

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK‑8931)

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core

Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via Intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura Coupling and Ring Closing Metathesis

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (<b>1</b>) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (<b>1</b>) has been achieved

Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin

A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (<b>1</b>) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael–lactolization–dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps