23 research outputs found
Iridium(III)-Catalyzed Regioselective C7-Amination of <i>N</i>āPivaloylindoles with Sulfonoazides
Direct
C7-amination of <i>N</i>-pivaloylindoles has been
achieved using a combination of [Cp*IrCl<sub>2</sub>]<sub>2</sub>,
AgNTf<sub>2</sub>, and AgOAc as the catalyst and sulfonoazides as
the nitrogen source. The reaction proceeded at room temperature to
80 Ā°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>āPivaloylindoles with Sulfonoazides
Direct
C7-amination of <i>N</i>-pivaloylindoles has been
achieved using a combination of [Cp*IrCl<sub>2</sub>]<sub>2</sub>,
AgNTf<sub>2</sub>, and AgOAc as the catalyst and sulfonoazides as
the nitrogen source. The reaction proceeded at room temperature to
80 Ā°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/CāO 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 CuĀ(I) catalyzed
CāO 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
ā¼100 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 Alzheimerās Disease
Verubecestat is an inhibitor of Ī²-secretase
being evaluated
for the treatment of Alzheimerās 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 CāN 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 (MKā8931)
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