Convenient approach for the synthesis of ONO-LB-457, a potent leukotriene B4 receptor antagonist. (1st January 2021)

• Record Type: Journal Article
• Authors: Hamri, Salha; Jouha, Jabrane; Oumessaoud, Asmaa; Pujol, M.D.; Khouili, Mostafa; Guillaumet, Gérald
• Is Part Of: Tetrahedron. Volume 77(2021)
• Publication Date: 2021-01-01
• Subjects: 5-Hydroxychroman-2-one -- 5-Bromovaleric acid -- Knoevenagel -- Wittig reaction -- Leukotriene B4 -- ONO-LB-457 -- Inflammatory; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2020.131740
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: This study reports a new approach for the synthesis of 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-(5 E )-hexen-1-yloxy]phenoxy]pentanoic acid V (ONO-LB-457), previously described by Konno and col. and which is considered a highly potent and orally active LTB4 receptor antagonist. This compound acts as an inhibitor of aggregation and chemotaxis, in addition to LTB4 -induced human neutrophil degranulation. In this work, the preparation of ONO-LB-457 was proposed through a convergent synthesis focused on the preparation of two fragments. First, the preparation of 5-hydroxychroman-2-one (4 ) from 2, 6-dimethoxybenzaldehyde and malonic acid, involving a Knoevenagel reaction, followed by a reduction of the olefin and intramolecular cyclization catalyzed by Lewis acid (tribromide) was achieved with an overall yield of 57%. Second, preparation of ( E )-6-(4-methoxyphenyl)hex-5-en-1-yl-methanesulfonate (18 ) from 5-bromovaleric acid (15 ) involving a Wittig reaction. The desired compound V (ONO-LB-457) was obtained by nucleophilic substitution of ( E )-6-(4-methoxyphenyl)hex-5-en-1-yl-methanesulfonate (18 ) with the ring-opened phenolic diester 14 followed by hydrolysis, in seven steps with an overall yield of about 11%. Graphical abstract: Image 1 Highlights: Synthetic route optimized for the preparation of ONO-LB-457. Preparation of 5-hydroxychroman-2-one from 2, 6-dimethoxybenzaldehyde. ONO-LB-457 is LTB4 receptor antagonist. BBr3 deprotects and lactonizes acid 14 in one step.