Alkylation of di-Boc-histidine methyl ester (III) with triflate (II) (prepared from 3-methyl-4-nitrobenzyl alcohol (I)) produced the intermediate imidazolium salt (IV) which, upon aqueous quenching with pH 7 phosphate buffer, led to the 3-substituted imidazole (V). Subsequent acid hydrolysis of the remaining N-Boc group of (V) furnished the 3-benzyl histidine (VI). Pictet-Spengler cyclization of (VI) with formaldehyde in the presence of HCl gave the corresponding imidazopyridine derivative, and further reesterification with trimethyl orthoformate led to the methyl ester (VII). Coupling of (VII) with diphenylacetic acid afforded amide (VIII). The nitro group of (VIII) was then reduced to aniline (IX) by catalytic hydrogenation in the presence of Raney Ni. Reductive alkylation of amine (IX) with formaldehyde and sodium cyanoborohydride yielded the dimethylamino derivative (X). The methyl ester group of (X) was finally hydrolyzed to the target carboxylic acid under basic conditions.

Alkylation of di-Boc-histidine methyl ester (III) with triflate (II) (prepared from 3-methyl-4-nitrobenzyl alcohol (I)) produced the intermediate imidazolium salt (IV) which, upon aqueous quenching with pH 7 phosphate buffer, led to the 3-substituted imidazole (V). Subsequent acid hydrolysis of the remaining N-Boc group of (V) furnished the 3-benzyl histidine (VI). Pictet-Spengler cyclization of (VI) with formaldehyde in the presence of HCl gave the corresponding imidazopyridine derivative, and further reesterification with trimethyl orthoformate led to the methyl ester (VII). Coupling of (VII) with diphenylacetic acid afforded amide (VIII). The nitro group of (VIII) was then reduced to aniline (IX) by catalytic hydrogenation in the presence of Raney Ni. Reductive alkylation of amine (IX) with formaldehyde and sodium cyanoborohydride yielded the dimethylamino derivative (X). The methyl ester group of (X) was finally hydrolyzed to the target carboxylic acid under basic conditions.