Process Development of C–N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib

Abstract

Process development of the synthesis of the orally active poly(ADP-ribose)polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed N-arylation of an indazole derivative as the late-stage fragment coupling step. Novel transaminase-mediated dynamic kinetic resolutions of racemic aldehyde surrogates provided enantioselective syntheses of the 3-aryl-piperidine coupling partner. Conversion of the C–N cross-coupling product to the final API was achieved by deprotection and salt metathesis to isolate the desired crystalline salt form.

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

“…Contemporary enzymatic approaches have risen to meet this demand in recent years. 6 These tools offer the potential to address the bulk production of material but still find developmental hurdles while engineering both high specificity and reactivity.…”

Why Leave a Job Half Done? Recent Progress in Enzymatic Deracemizations

“…[91] Also, a lactam precursor of niraparib, an anticancer drug, was obtained through amination of a racemic aldehyde that intramolecularly cyclized in a cascade fashion. [92] …”

Asymmetric Amination of α‐Chiral Aliphatic Aldehydes via Dynamic Kinetic Resolution to Access Stereocomplementary Brivaracetam and Pregabalin Precursors

“…The forma-tion of side products and/or the unwanted enantiomer is also an issue regarding the classical manufacturing route towards Pregabalin developed by Pfizer, [9] where the amine is prepared in racemic form and the targeted (S)-enantiomer is obtained via diastereomeric salt formation with mandelic acid. Reports of transaminase mediated amination of a-chiral aldehydes [52][53][54][55] prior to this work are scarce and focus on substrates bearing the a-stereocentre in benzylic position. [10][11] Recently, biocatalysis has contributed significantly to the synthesis of APIs [12][13][14][15][16] and a vast number of methods involving ene-reductases, [17][18][19] nitrilases [20][21][22] and tautomerases [23] were established serving as alternative enzymatic routes towards Pregabalin via asymmetric synthesis or resolution of enantiomers.…”