Convenient approach for the synthesis of ONO-LB-457, a potent leukotriene B4 receptor antagonist

TETRAHEDRON

卷:77

Article

Hamri, Salha^1,4  Jouha, Jabrane^1,3  Oumessaoud, Asmaa^1,2  Pujol, M. D.²  Khouili, Mostafa¹  Guillaumet, Gerald³ 

[1] Univ Sultan Moulay Slimane, Fac Sci & Tech, Lab Chim Organ & Analyt, BP 523, Beni Mellal 23000, Morocco

[2] Univ Barcelona, Fac Farm, Lab Quim Farmaceut, Barcelona 08028, Spain

[3] Univ Orleans, Inst Chim Organ & Analyt, UMR CNRS 7311, BP 6759,Rue Chartres, F-45067 Orleans 2, France

[4] Univ Ibn Zohr, Fac Sci, Lab Chim Organ Organometall & Valorisat Subst Nat, BP 8106, Cite Dakhla 80000, Agadir, Morocco

关键词: 5-Hydroxychroman-2-one;    5-Bromovaleric acid;    Knoevenagel;    Wittig reaction;    Leukotriene B-4;    ONO-LB-457;    Inflammatory;   

DOI  :  10.1016/j.tet.2020.131740

来源: Elsevier

【 摘 要 】

This study reports a new approach for the synthesis of 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-(5E)-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%. (C) 2020 Elsevier Ltd. All rights reserved.

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