The deprotection of the resin (I) with piperidine in DMF gives the amino-resin (II), which is condensed with N-Fmoc-L-proline (III) by means of diisopropylcarbodiimide (DIC) in DMF to yield the anchored proline (IV). The deprotection of (IV) with piperidine in DMF affords compound (V) with a free NH group, which is condensed with 2-bromoacetic acid (VI) by means of DIC DMF to provide the bromoacetyl proline resin (VII). The condensation of (VII) with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in DMSO to give the resin anchored precursor (IX), which is finally cleaved by means of trifluoroacetic anhydride (TFAA) in THF to furnish the target pyrrolidine-carbonitrile. Alternatively, the acylation of L-prolinamide (X) with 2-bromoacetyl bromide (XI) by means of TEA and DMAP in dichloromethane gives the 1-(2-bromoacetyl)-L-prolinamide (XII), which is dehydrated by means of TFAA in dichloromethane to yield the pyrrolidine-carbonitrile (XIII). Finally, this compound is condensed with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in THF to furnish the target pyrrolidine-carbonitrile.
The reaction of 6-chloropyridine-3-carbonitrile (I) with carbamate (II) by means of KHCO3 in hot DMF gives the adduct (III), which is treated with TFA in dichloromethane to yield 6-(2-aminoethylamino)pyridine-3-carbonitrile (IV). The cyclization of (IV) with formaldehyde affords 6-(1-imidazoldinyl)pyridine-3-carbonitrile (V), which is condensed with 1-(2-bromoacetyl)piperidine-2(S)-carbonitrile (VI) by means of TEA in THF to provide the adduct (VII). Finally, the cleavage of the imidazolidine ring of (VII) by means of TFA in water, or TFA and 3-(4-(hydrazinosulfonyl)phenyl)propionyl AM resin in dichloromethane, gives rise to the target pyridine-carbonitrile derivative.
The condensation of protected L-proline (I) with RINK RESIN (II) by means of TBTU, HOBT and DIEA in DMF gives the protected, rein bounded proline (III), which is deprotected by means of piperidine in DMF to yield the resin bounded proline (IV). The condensation of (IV) with 2-bromoacetic acid (V) by means of DIC in the same solvent affords the acyl proline (VI), which is treated with ethylene-1,2-diamine (VII) to provide the aminoacetyl proline (VIII). The condensation of (VIII) with 2-acetyldimedone (IX) gives the regioselectively monoprotected diaminoproline compound (X), which is treated with Boc2O and DIEA in dioxane to protect the secondary amino group of (X) and yield (XI). The selective elimination of the dimedone protecting group with hydrazine in DMF affords compound (XII) selectively monoprotected at the secondary amino group, which is condensed with 6-chloropyridine-3-carbonitrile (XIII) by means of DIEA in NMP to provide the resin adduct (XIV). The cleavage of the resin group of (XIV) by means of TFA and TFAA in dichloromethane takes place with simultaneous dehydration of the carboxamide group and removal of the Boc protecting group affording the trifluoroacetamido derivative (XV). Finally, the trifluoroacetyl group is removed by means of NH3 in aqueous methanol to give rise to the target pyridine carbonitrile derivative.