合成路线1

The reduction of 4-bromophenylacetic acid (I) with boron hydride gives 2-(4-bromophenyl)ethanol (II), which is mesylated with methanesulfonyl chloride to the sulfonate (III). The condensation of (III) with diethyl malonate (IV) by means of NaH yields 2-[2-(4-bromophenyl)ethyl]malonic acid diethyl ester (V), which is reduced with LiAlH4 to the diol (VI). The enantioselective transesterification of (VI) with methyl acetate by means of porcine pancreatic lipase (PPL, Sigma type II, no. 3126) affords the (R)-enantiomer of monoester (VII), which is treated with tert-butyldimethylsilyl chloride in dichloromethane, giving the (S)-enantiomer of the silylated acetoxy derivative (VIII). The hydrolysis of (VIII) with methanolic NaOH yields the silylated alcohol (IX), which is mesylated with methanesulfonyl chloride as before affording the sulfonate (X). The reaction of (X) with sodium azide in hot DMF gives 1-azido-4-(4-bromophenyl)-2(S)-(tert-butyldimethylsilyloxymethyl)butane (XIII), which is deprotected with acetic acid in THF yielding 2(S)-(azidomethyl)-4-(4-bromophenyl)butanol (XII). Mesylation of (XII) as before affords sulfonate (XIII), which is condensed with diethyl malonate (IV) by means of NaH as before, giving the chiral malonate derivative (XIV). The cyclization of (XIV) by means of tributyl phosphine in THF yields (3RS,5R)-5-[2-(4-bromophenyl)ethyl]-2-oxopiperidine-3-carboxylic acid ethyl ester (XV), which is treated with trimethyloxonium tetrafluoroborate in CHCl3 to afford the methoxy derivative (XVI). Cyclization of (XVI) with guanidine hydrochloride (XXII) by means of sodium ethoxide in hot ethanol gives 2-amino-6(R)-[2-(4-bromophenyl)ethyl]-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (XVII), which is treated with copper cyanide in refluxing 1-methyl-2-pyrrolidone, yielding the nitrile (XVIII). Hydrolysis of (XVIII) with refluxing 6N HCl affords the corresponding benzoic acid (XIX), which is condensed with L-glutamic acid diethyl ester (XX) by means of N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine in DMF, affording the diethyl ester of the desired product (XXI). Finally, this compound is hydrolyzed with 1N NaOH.