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

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Abstract 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%.