合成路线1

The hydrogenation of 4-isopropylbenzoic acid (I) with H2 over PtO2 in acetic acid gives 4-isopropylcyclohexanecarboxylic acid as a mixture of cis- and trans-isomers (II). This mixture is esterified with methanol to the corresponding mixture of methyl esters (III), which is isomerized with NaH at 150 C without solvent, affording the trans-methyl ester (IV). Hydrolysis of (IV) with NaOH in methanol - water gives the free acid (V), which is finally condensed with D-phenylalanine (VI) by means of N-hydroxysuccinimide and dicyclohexylcarbodiimide in chloroform.

合成路线2

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).

合成路线3

D-Phenylalanine (I) was protected as the methyl carbamate (II) by acylation with methyl chloroformate under Schotten-Baumann conditions. The N-methoxy amide (III) was then prepared by coupling of (II) with O-methyl hydroxylamine in the presence of EDC. Cyclization of (III) to the N-methoxy quinolinone (IV) was accomplished by treatment with bis(trifluoroacetoxy)iodobenzene in the presence of trifluoroacetic acid. Simultaneous reduction of the N-methoxy lactam and carbamate functions of (IV) by means of borane-methyl sulfide complex provided diamine (V). The aliphatic amino group of (V) was then selectively protected as the benzyl carbamate (VI) by using N-(benzyloxycarbonyloxy)succinimide at -40 C. Reaction of (VI) with phosgene, followed by treatment of the intermediate carbamoyl chloride with O-methyl hydroxylamine gave rise to the N-methoxy urea derivative (VII). This was cyclized with bis(trifluoroacetoxy)iodobenzene to the imidazoquinolinone (VIII). The N-methoxy and N-benzyloxycarbonyl groups of (VIII) were then removed by hydrogenolysis in the presence of Pearlman's catalyst, and the title compound was finally converted to the corresponding maleate salt.

合成路线4