Benzocycloheptapyridine (I) was nitrated with NaNO3 and H2SO4 to afford (II) as the major isomer. Reduction of (III) with iron and CaCl2 gave amine (III), which was brominated to provide (IV). Removal of the amino group of (IV) was accomplished by diazotization, followed by reduction with hypophosphorous acid to give (V). Then, hydrolysis of the carbamate group of (V) in refluxing hydrochloric acid furnished piperidine (VI). Subsequent coupling of (VI) with pyridineacetic acid N-oxide (VII) using EDC and HOBt yielded the corresponding amide. Finally, separation of the target (+)-atropoisomer was achieved by chiral chromatography.
Benzocycloheptapyridine (I) was nitrated with NaNO3 and H2SO4 to afford (II) as the major isomer. Reduction of (II) with iron and CaCl2 gave amine (III), which was brominated to provide (IV). Removal of the amino group of (IV) was accomplished by diazotization, followed by reduction with hypophosphorous acid to give (V). Then, hydrolysis of the carbamate group in refluxing hydrochloric acid furnished piperidine (VI). Subsequent coupling of (VI) with N-Boc-piperidineacetic acid (VII) using EDC and HOBt yielded amide (VIII). After Boc deprotection of (VIII) with trifluoroacetic acid, piperidine (IX) was condensed with trimethylsilyl isocyanate to produce the corresponding urea. Finally, separation of the target (+)-atropoisomer was achieved by chiral chromatography.
Introduction of a bromine atom at the 10-position of the benzocycloheptapyridine (I) was achieved by the following sequence. Nitration of (I) using NaNO3-H2SO4 afforded a mixture of nitro compounds (II) and (III), from which the major 9-nitro isomer (III) was separated by silica gel chromatography. Reduction of the nitro group of (III) with iron filings and CaCl2 in refluxing aqueous ethanol gave amine (IV), which was brominated at position 10 with Br2 in AcOH. The brominated aniline (VI) was then deaminated by diazotization, followed by reduction of the resulting diazonium salt with hypophosphorous acid to give trihalo compound (VI). Hydrolysis of carbamate group of (VI) in boiling concentrated HCl afforded piperidine (VII). Subsequent reduction of the C-11 double bond of (VII) was carried out using DIBAL-H in refluxing toluene to afford the corresponding racemic piperidine. Separation of enantiomers was achieved by HPLC on a ChiralPak AD column or by chemical resolution using N-acetyl-L-phenylalanine as the resolving agent. The appropriate R-(+) enantiomer (VIII) was coupled with N-Boc-piperidylacetic acid (IX) in the presence of EDC and HOBt to yield protected amide (X). Hydrolysis of the Boc protecting group was performed with trifluoroacetic acid, and the resulting piperidine (XI) was finally treated with trimethylsilyl isocyanate to give the desired carboxamide (3-5).