Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor

Abstract

Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber–Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.

Synthesis of 3,4-Fused Tricyclic Indoles through Cascade Carbopalladation and C–H Amination: Development and Total Synthesis of Rucaparib

“…It was approved by the FDA as Rubraca (rucaparib camsylate) for the treatment of ovarian cancer in 2016 . Only several syntheses of rucaparib have been reported, and they generally follow two strategies (Figure ): (1) The 3,4-fused tricyclic indoles are constructed from 6-fluoro indole derivatives, and the 4-((methylamino)­methyl)­phenyl group is introduced at a late stage. , The synthesis of 6-fluoro indole derivatives requires multiple steps, and the installation of a functional group to the three- or four-positions of the indoles is often low-yielding. Furthermore, an additional brominating reaction is needed to introduce the 4-((methylamino)­methyl)­phenyl group.…”

Small-Molecule Anti-Cancer Drugs From 2016 to 2020: Synthesis and Clinical Application

“…29,89 The most likely synthetic approach to rucaparib (XXXI) camsylate is described in Scheme 32. 90 Starting material 305 was treated with aqueous HCl to obtain 306 in 62% yield. This was followed by methyl 6-fluoro-1H-indole-4carboxylate (307) treatment to obtain 308.…”

Patent Review of Manufacturing Routes to Recently Approved PARP Inhibitors: Olaparib, Rucaparib, and Niraparib

“…A publication from the Pfizer process chemistry group describes the second Process Chemistry route to rucaparib, which involved modifications to the original Medicinal Chemistry route outlined in Scheme 6. 35 Perhaps unable to reproduce the one-step conversion of 16 to nitroalkane 17, this chemistry was replaced with a two-step process using reaction with 1-(dimethylamino)-2-nitroethylene followed by reduction with sodium borohydride, which only proceeded in 33% yield (Scheme 8).…”

“…The final form of rucaparib is an anhydrous (S)-camphorsulfonic acid salt, commonly referred to as the "camsylate salt". Three polymorphs of the camsylate salts were discovered, denoted as Forms A, B, and C. 39 On the basis of information in the patents 39 and the Pfizer publication, 35 Form A appears to be the most stable polymorph (highest melting) and is the form generated from the crystallization process using 2-PrOH/water. The phosphate salt was used for early clinical trials in which the drug was administered intravenously.…”

“…Three polymorphs of the camsylate salts were discovered, denoted as Forms A, B, and C . On the basis of information in the patents and the Pfizer publication, Form A appears to be the most stable polymorph (highest melting) and is the form generated from the crystallization process using 2-PrOH/water.…”