The intermediate protected sulfonamide (IV) was prepared by condensation of 2-bromobenzenesulfonyl chloride (I) with 5-amino-3,4-dimethylisoxazole (II), followed by protection of the resulting sulfonamide (III) with (2-methoxyethoxy)methyl chloride and NaH.
Reaction of 1-bromo-4-isobutylbenzene (V) with magnesium generated the corresponding Grignard reagent (VI), which was condensed with trimethyl borate to afford, after acid hydrolysis, arylboronic acid (VII). This was nitrated with acetyl nitrate to produce nitro derivative (VIII). Subsequent reduction of the nitro group of (VIII) by hydrogenation over Pd/C gave 2-amino-4-isobutylphenyl boronic acid (IX). Suzuki coupling of boronic acid (IX) with bromosulfonamide (IV) produced the required biphenyl (X). The methoxyethoxymethyl group was finally deprotected by treatment with HCl to furnish the title compound.
In an alternative procedure, Wittig reaction of 3-nitrobenzaldehyde (XI) with isopropyltriphenylphosphonium iodide gave isobutenyl compound (XII). Then, the nitro group of (XII) was selectively reduced to aniline (XIII) by hydrogenation over Pt/C, and this was protected as the pivaloyl amide (XIV) with pivaloyl chloride. Further hydrogenation of (XIV) using Pd/C produced the isobutyl derivative (XV). Lithiation of (XV) with tert-butyllithium generated the intermediate organolithium reagent (XVI), which was subsequently converted to boronic acid (XVII). Further Suzuki coupling of (XVII) with bromosulfonamide (IV) produced biphenyl (XVIII). Reductive removal of the pivaloyl group of (XVIII) using DIBAL-H then gave the precursor (X), which was finally deprotected with HCl to afford the target compound.