An Efficient Process for Synthesis of 3-(R)-3-(2,3-Dihydrobenzofuran-5-yl)- 1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one

Abstract

3-(R)-3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4-b]quinolin-9-one (1) is a key intermediate in the synthesis of pyrroloquinolone analogues, a series of highly potent and selective phosphodiesterase 5 (PDE5) inhibitors. Racemic 1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (6, Scheme 2) was prepared by Pictet−Spenger condensation in 84% isolated yield with >97% chemical purity. The desired intermediate, 1-(R)-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline N-acetyl-d-leucine salt (8), was obtained in 35% isolated yield with high chiral purity (≥ 97% ee) from the chemical resolution of 6 with N-acetyl-d-leucine (7). A racemization step was developed for recycling enriched 1-(S)-β-carboline 9 freebase (8/9, 25 ± 3%/75 ± 3%) to a near racemic mixture (8/9, 47 ± 1%/53 ± 1%). Furthermore, the resolving reagent 7 was recovered in >76% yield, which, together with the recycled racemic mixture (8/9, 47 ± 1%/53 ± 1%), afforded 35% more salt 8 after two recycles (...