Compound (I) is nitrated employing KNO3 in cold H2SO4 to produce (II). Subsequent nitro group reduction in (II) to afford amine (III) is carried out by means of iron powder in the presence of CaCl2. Bromination of (III) in AcOH then gives (IV). The amino group of (IV) is removed via diazotization with t-butyl nitrite in hot DMF to furnish (V). Further acidic hydrolysis of the ethyl carbamate group of (V) leads to amine (VI). Double bond reduction in (VI) by means of DIBAL in toluene, followed by resolution of the resultant racemic mixture by chiral preparative HPLC provides intermediate (VII) (1,2).
Amine (VII) is coupled to N-Boc-4-piperidineacetic acid (VIII) by means of EDC/HOBt to afford amide (IX). Subsequent acidic cleavage of the N-Boc group of (IX) leads to amine (X) (1,2). Piperidine (X) is finally coupled with malonic acid mono-amide (XI) to furnish the title compound (1,2). In a related method, piperidine (X) is coupled to mono-methyl malonate (XII), yielding the amide ester (XIII). Basic hydrolysis of the methyl ester group of (XIII) then leads to the sodium carboxylate salt (XIV), which is finally reacted with ammonium chloride in the presence of EDC/HOBt to produce the target amide (3).