合成路线1

CP-72467-2 has been prepared by two synthetic routes which share a common intermediate. 1) In the initial route, diazotization of D-phenylalanine followed by esterification afforded the methyl ester of (R)-phenyllactic acid (I). Mitsunobu coupling with methyl 4-hydroxybenzoate using diisopropyl azodicarboxylate, selective reduction with sodium borohydride, and conversion to the bromide by in situ generation of triphenylphosphine dibromide produced intermediate (II). Friedel-Crafts alkylation of (II) using alpha-hydroxyhippuric acid/methanesulfonic acid, azalactone formation with acetic anhydride/triethylamine, followed by in situ spiroalkylation produced the N-benzoyl amino acid (III). Oxidative decarboxylation of (III) with 15% sodium hypochlorite led to the chromanone (V), presumably through hydrolysis of the intermediate N-benzoyl imine (IV). Catalytic hydrogenation over 10% Pd on carbon of the chromanone (V), reduction of the ester with Red-Al, and subsequent oxidation of the alcohol with manganese dioxide afforded the key aldehyde intermediate (VI). Condensation of aldehyde (VI) with 2,4-thiazolidinedione/pyridine, catalytic hydrogenation of the resultant olefin, and salt formation with sodium methoxide produced CP-72467-2. 2) An alternative synthesis of the key intermediate aldehyde (VI) utilizes an enzymatic resolution of the benzopyran ester (VII). Reduction of the 2(R)-ester with sodium borohydride followed by reaction with triflic anhydride generates the triflate (VIII). Copper-catalyzed reaction of the triflate (VIII) with phenyl magnesium bromide afforded the benzyl derivative (IX), which is readily formylated with phosphorous oxychloride/N-methyl formanilide to produce aldehyde (VI).