An Efficient Process for Synthesis of 3-(<i>R</i>)-3-(2,3-Dihydrobenzofuran-5-yl)- 1,2,3,4-tetrahydropyrrolo[3,4-<i>b</i>]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-1 H -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-1 H - 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 (≥97.0% ee). The salt 8 was converted to 1-( R )-1-(2,3-dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1 H -β-carboline ( 10 ) in excellent yield (94%). A modified Winterfeldt oxidation of compound 10 using Aliquat 175 as a phase transfer catalyst produced 3-( R )-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4- b ]quinolin-9-one ( 12 ) in moderate 42% yield. Hydrogenolysis of compound 12 gave the desired compound 1 in quantitative yield with retention of chiral purity (≥97.0% ee). This efficient, reproducible, economical, and nonchromatography scale-up process could be used to make multikilogram quantities of compound 1 .