Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor

Abstract

Compound (1) a poly(ADP-ribose)polymerase (PARP) inhibitor has been made by a fit-for-purpose large-scale synthesis using either a classical resolution or chiral chromatographic separation. The development and relative merits of each route are discussed, along with operational improvements and extensive safety evaluations of potentially hazardous reactions.

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

“…The medicinal chemistry approach to niraparib involved the tartaric acid salt of a 3-aryl piperidine and inefficient resolution via multiple crystallizations (20% yield, 80–90% ee), followed by chiral HPLC purification at a later stage49. For the large scale synthesis Merck first developed an approach based on chiral HPLC separation of rac - 83 (46% yield, 94% ee) capable of 0.27 Kg separated product per Kg stationary phase per day (Fig.…”

Cobalt-Catalyzed (Hetero)arylation of Saturated Cyclic Amines with Grignard Reagents

“…Among the saturated N -heterocycles, 4-arylpiperidines, 3-arylpiperidines, 3-arylpyrrolidines and 3-arylazetidines are attractive scaffolds in drug discovery, exhibiting a broad range of biological activities [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Due to these interesting properties, numerous methods have been developed to access these aryl substituted N -heterocycles, either through ring formation or arylation of cyclic compounds [ 9 , 10 , 11 , 12 , 13 ].…”

Cobalt‐Catalyzed Cross‐Coupling of 3‐ and 4‐Iodopiperidines with Grignard Reagents

“…Paroxetine is an antidepressant2 and naratriptan is used in the treatment of migraine headaches 3. Preclamol is an antipsychotic drug4 and MK‐4827 inhibits poly(adenosine diphosphate ribose) polymerase, an enzyme responsible for DNA repair that plays a role in several cancers 5…”

“…[3] Preclamol is an antipsychoticd rug [4] and MK-4827 inhibits poly(adenosine diphosphater ibose) polymerase, an enzyme responsible for DNA repair that plays ar ole in several cancers. [5] The potent biological activities of substituted piperidines arousedt he interest of organic chemists and important efforts have been dedicatedt ot he synthesis of substituted piperidines. [6] Among them,t he direct functionalization of the piperidine ring through modular metal-catalyzed cross-couplings appeareda sapowerful strategyt og enerate molecular diversity from halogeno derivatives.…”