Intramolecular Diels-Alder reaction of the N-pyrazinylmethyl-N-propargyl carbamate (I), with subsequent extrusion of HCN, gave rise to a mixture of the isomeric pyrrolopyridines (II) and (III). Acidic hydrolysis of the pyrrolo[3,4-b]pyridine carbamate (III) provided the bicyclic amine (IV). This was condensed with 3,4-difluoronitrobenzene (V) to give the aryl amine (VI). Catalytic hydrogenation of the nitro group of (VI) yielded aniline (VII), which was converted to the benzyl carbamate (VIII) upon treatment with benzyl chloroformate. The chiral oxazolidinone (X) was then obtained by condensation of the lithium salt of carbamate (VIII) with (R)-glycidyl butyrate (IX) at -78 C. Conversion of alcohol (X) to mesylate (XI), and subsequent mesylate displacement with NaN3 in hot DMF, furnished azide (XII). Finally, hydrogenation of azide (XII) to the corresponding amine, followed by acylation with Ac2O, led to the target acetamide.
Intramolecular Diels-Alder reaction of the N-pyrazinylmethyl-N-propargyl carbamate (I), with subsequent extrusion of HCN, gave rise to a mixture of the isomeric pyrrolopyridines (II) and (III). Acidic hydrolysis of the pyrrolo[3,4-c]pyridine carbamate (III) provided the bicyclic amine (IV). This was condensed with 3,4-difluoronitrobenzene (V) to give the aryl amine (VI). Catalytic hydrogenation of the nitro group of (V) yielded aniline (VII), which was converted to the benzyl carbamate (VIII) upon treatment with benzyl chloroformate. The chiral oxazolidinone (X) was then obtained by condensation of the lithium salt of carbamate (VIII) with (R)-glycidyl butyrate (IX) at -78 C. Conversion of alcohol (X) to mesylate (XI), and subsequent mesylate displacement with NaN3 in hot DMF, furnished azide (XII). Finally, hydrogenation of azide (XII) to the corresponding amine, followed by acylation with Ac2O, led to the target acetamide.
Condensation of pyrrolidinone (XIII) with methoxy-bis(dimethylamino)methane gives the beta-ketoenamine (XIV). Then, cyclization of (XIV) with 2 amidinopyridine (XV) generates the target pyrrolopyrimidine system.
After protection of 1-benzyl-3-pyrrolidinone (I) as the corresponding ethylene ketal (II) with ethylene glycol and p-toluenesulfonic acid, N-benzyl group hydrogenolysis over Pearlman's catalyst provides the secondary amine (III). Subsequent condensation of amine (III) with 3,4-difluoronitrobenzene (IV) in hot DMF furnishes the N-aryl pyrrolidine (V). Reduction of the nitro group of (V) by transfer hydrogenation with ammonium formate and Pd/C leads to aniline (VI). This is further acylated with benzyl chloroformate producing carbamate (VII). Then, reaction of the lithium anion of carbamate (VII) with (R)-glycidyl butyrate (VIII) gives rise to oxazolidinone (IX). After conversion of alcohol (IX) to mesylate (X), the primary amine (XI) is obtained by Gabriel synthesis with potassium phthalimide, followed by hydrazinolysis. Acylation of amine (XI) with Ac2O produces amide (XII). The ethylene ketal of (XII) is then hydrolyzed with p toluenesulfonic acid in aqueous acetone, providing pyrrolidinone (XIII).