Novel Approaches towards the LTD₄/E₄ Antagonist, LY290154

Abstract

Several novel approaches have been investigated for the synthesis of the LTD4/E4 antagonist LY290154. Significant improvements to the discovery route were first made by using an indoline nucleophile instead of an indolyl anion in the key substitution step. An alternative approach, introducing the 7-chloroquinoline moiety in the latest stages of the synthesis was then demonstrated. Interestingly, the pivotal intermediate of this latter route was also obtained in a one-pot process following a Katritzky methodology. Finally, an asymmetric synthesis offering significant advantages over the enantioselective route reported by McKillop was demonstrated.

Applications of Bartoli indole synthesis

“…124 Scheme 37 Synthesis of 7-cyanomethoxyindole. 125 Scheme 38 Synthesis of the 4-fluoro-6-azaindole core, a key intermediate for preparation of HIV-1 attachment inhibitors. 134 Scheme 39 Synthesis of azaindole derivatives for SAR of the cannabinoid receptor agonist.…”

Lewis‐Acid‐Catalyzed Benzylic Reactions of 2‐Methylazaarenes with Aldehydes

“…[1] Therefore, functionalized pyridines and related azaarenes play increasingly important roles in natural compounds synthesis and drug discovery. [3] In addition, 2-alkenylyridine derivatives are not only ubiquitous structural motifs in biologically relevant molecules -for example, CGS23114 (4)but also serve as valuable precursors for a wide range of 2-alkylpyridines and piperidines, themselves of significant biological importance, [4] whereas 2-alkenylquinolines, especially those containing the (7-chloroquinolin-2-yl)vinylphenyl moiety, are always present in the leukotriene receptor antagonists (LTRAs), such as montelukast (5), L-660,711 (6), and LY290154 (7), used for the treatment of asthma. [3] In addition, 2-alkenylyridine derivatives are not only ubiquitous structural motifs in biologically relevant molecules -for example, CGS23114 (4)but also serve as valuable precursors for a wide range of 2-alkylpyridines and piperidines, themselves of significant biological importance, [4] whereas 2-alkenylquinolines, especially those containing the (7-chloroquinolin-2-yl)vinylphenyl moiety, are always present in the leukotriene receptor antagonists (LTRAs), such as montelukast (5), L-660,711 (6), and LY290154 (7), used for the treatment of asthma.…”

“…[2] Among them, as depicted in Figure 1, 2-(pyridin-2-yl)ethanols are precursors of sedamine (1), lobeline (2), and lobenlanidine (3), which are members of a large and diverse group of alkaloids found particularly in lobelia and sedum alkaloids, and are widely used as drugs. [5] It is not surprising, therefore, that great efforts have been directed toward developing synthetic approaches for the construction of derivatives of pyridine and other aza-for improving the yield (Entries 2-7). [5] It is not surprising, therefore, that great efforts have been directed toward developing synthetic approaches for the construction of derivatives of pyridine and other aza-for improving the yield (Entries 2-7).…”

“…Considering the wide application of 2-alkenylquinolines in the synthesis of medical compounds, [5] further modification of the reaction conditions, especially with regard to the catalyst, was adopted to improve the yield of 4ca. As outlined in Table 3, when Cu(OTf) 2 was employed, the product was isolated in only 14 % yield (Entry 2).…”

Synthesis and acid-base properties of bifunctional compounds based on 2-styrylquinoline and 6-hydroxynaphthalene-2-carboxylic acid

“…Persistent interest in various 2-styrylquinoline derivatives is determined by the wide spectrum of their applications related to different kinds of biological activity [1][2][3][4] and diversity of photochemical reactions and luminescent and photochemical properties, as well as by the possibility of controlling them by varying the structure of compounds [5][6][7][8]. 6-Hydroxynaphthalene-2-carboxylic acid derivatives are precursors of liquid crystals [9,10].…”