3 research outputs found
Regioselective Synthesis of Substituted 4‑Alkylamino and 4‑Arylaminophthalazin-1(2<i>H</i>)‑ones
An
efficient regioselective synthesis of substituted 4-alkylamino
and 4-arylaminophthalazin-1Â(1<i>H</i>)-ones <b>5</b> is described. This new method features the formation of substituted
phthalazin-1Â(1<i>H</i>)-ones <b>3</b> by the reaction
of 2-formylbenzoic acids <b>1</b> or 3-hydroxyisobenzofuran-1Â(3<i>H</i>)-ones <b>2</b> with hydrazine to generate phthalazin-1Â(2<i>H</i>)-ones <b>3</b>. Subsequent regioselective bromination
of phthalazin-1Â(2<i>H</i>)-ones <b>3</b> with benzyltrimethylammonium
tribromide (BTMA-Br<sub>3</sub>) followed by mixed copper–copper
oxide-catalyzed amination of 4-bromophthalazin-1Â(2<i>H</i>)-ones <b>4</b> with primary amines generates aminophthalazin-1Â(2<i>H</i>)-ones in good overall yields
Development of the Large-Scale Synthesis of Tetrahydropyran Glycine, a Precursor to the HCV NS5A Inhibitor <b>BMS-986097</b>
An efficient large-scale
synthesis of acid <b>1</b>, a penultimate
precursor to the HCV NS5A inhibitor <b>BMS-986097</b>, along
with the final API step are described. Three routes were devised for
the synthesis of <b>1</b> at the various stages of the program.
The third generation route, the one that proved scalable and is the
main subject of this paper, features a one-step Michael addition of <i>t</i>-butyl 2-((diphenylmethylene)Âamino)Âacetate (<b>24</b>) to (<i>E</i>)-benzyl 4-(1-hydroxycyclopropyl)Âbut-2-enoate
(<b>28</b>) followed by cyclization and chiral separation to
form <b>27c</b>, the core skeleton of cap piece <b>1</b>. The epimerization and chiral resolution of <b>27c</b> followed
by further synthetic manipulations involving the carbamate formation,
lactone reduction and cyclization, afforded cyclopropyl pyran <b>1</b>. A detailed study of diphenylmethane deprotection via acid
hydrolysis as well as a key lactone to tetrahydropyran conversion,
in order to avoid a side reaction that afforded an alternative cyclization
product, are discussed. This synthesis was applied to the preparation
of more than 100 g of the final API <b>BMS-986097</b> for toxicology
studies
Discovery of 6‑Fluoro-5‑(<i>R</i>)‑(3‑(<i>S</i>)‑(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4<i>H</i>)‑yl)-2-methylphenyl)-2‑(<i>S</i>)‑(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro‑1<i>H</i>‑carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers
Bruton's tyrosine
kinase (BTK), a nonreceptor tyrosine kinase,
is a member of the Tec family of kinases. BTK plays an essential role
in B cell receptor (BCR)-mediated signaling as well as FcÎł receptor
signaling in monocytes and Fcε receptor signaling in mast cells
and basophils, all of which have been implicated in the pathophysiology
of autoimmune disease. As a result, inhibition of BTK is anticipated
to provide an effective strategy for the clinical treatment of autoimmune
diseases such as lupus and rheumatoid arthritis. This article details
the structure–activity relationships (SAR) leading to a novel
series of highly potent and selective carbazole and tetrahydrocarbazole
based, reversible inhibitors of BTK. Of particular interest is that
two atropisomeric centers were rotationally locked to provide a single,
stable atropisomer, resulting in enhanced potency and selectivity
as well as a reduction in safety liabilities. With significantly enhanced
potency and selectivity, excellent in vivo properties and efficacy,
and a very desirable tolerability and safety profile, <b>14f</b> (BMS-986142) was advanced into clinical studies