Selective O-alkylation of trans-4-aminocyclohexanol (I) was effected by protection of the amino group as the triazinone (III) upon treatment with N,N-dimethylurea and formaldehyde. Subsequent alkylation of (III) with tert-butyl bromoacetate under phase-transfer conditions afforded ether (IV). The protecting group of (IV) was then removed by treatment with ammonium chloride.
Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (VI) gave imidate (VII) and subsequent treatment with ethanolic ammonia afforded amidine (VIII). After basic hydrolysis of the ester group of (VIII), protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IX). Coupling of (IX) with aminoester (V) in the presence of EDC and HOBt yielded amide (X). Sequential cleavage of benzyloxycarbonyl and tert-butyl groups orf (X) provided amidino acid (XI), which was finally esterified with EtOH and methanesulfonic acid.
Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (I) gave imidate (II) and subsequent treatment with ethanolic ammonia afforded amidine (III). After basic hydrolysis of the ester group of (III), protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IV). Coupling of (IV) with ethyl trans-3-(4-aminocyclohexyl)propionate (V) in the presence of EDC and HOBt yielded amide (VI). Finally, hydrogenolysis of the benzyloxycarbonyl protecting group of (VI) provided the title amidino ester.