5-Aminoindan (I) was acetylated, and the resulting anilide (II) was brominated in HOAc to afford (III). Displacement of the bromine of (III) with CuCN in N-methylpyrrolidinone at 125 C furnished nitrile (IV), which was cyclized to the desired quinazolinone derivative (V) upon treatment with sodium hydroperoxide. Protection of the NH group of (V) was achieved by alkylation with chloromethyl pivaloate yielding (VI). Benzylic bromination of (VI) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromide (VII). This was condensed with diethyl p-aminobenzoyl-L-glutamate (VIII) by means of CaCO3 to produce adduct (IX). Further alkylation of (IX) with propargyl bromide (X) using CaCO3 provided propargyl amine (XI). Hydrolysis of the ethyl esters and pivaloyloxymethyl protecting group of (XI) with NaOH afforded (XII). The glutamic acid moiety of (XII) was then removed by enzimatic hydrolysis with carboxypeptidase G2 to furnish intermediate (XIII).
N-(Benzyloxycarbonyl)-D-glutamic acid (XIV) was converted to the mixed anhydride (XV) with isobutyl chloroformate and then treated with ammonia to give amide (XVI). Dehydration of the amide with POCl3/pyridine produced nitrile (XVII) and further dipolar cycloaddition of NaN3 produced the tetrazole (XVIII). After hydrogenolysis of the benzyloxycarbonyl protecting group of (XVIII), the resulting amine (XIX) was coupled with N-(benzyloxycarbonyl)-L-glutamic acid (XX) via activation as the mixed anhydride with isobutyl chloroformate to give (XXI). The benzyloxycarbonyl group of (XXI) was then deprotected by catalytic hydrogenolysis over Pd/C as above, yielding amine (XXII). This was coupled with the intermediate benzoic acid derivative (XIII) employing benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate to furnish amide (XXIII). The tert-butyl esters of (XXIII) were finally cleaved by treatment with trifluoroacetic acid.