Development of a Suitable Process for the Preparation of a TNF-α Converting Enzyme Inhibitor, WAY-281418

Abstract

A suitable process for the preparation of kilogram quantities of a TNF-r converting enzyme (TACE) inhibitor (WAY-281418) was developed using isatin 13 as starting material and an efficient coupling step for the formation of sulfonamide 8 in a 15% overall yield. Process preparation of (+)-(1S,2R)-2-aminocyclopentane-1carboxylic acid (7, (+)-cispentacin), a chiral component for WAY-281418, was successfully scaled up via an asymmetric hydrogenation reaction. Crystallization allowed the isolation of all intermediates and the final product 9.

High-performance liquid chromatographic enantioseparation of cyclic β-aminohydroxamic acids on zwitterionic chiral stationary phases based on Cinchona alkaloids

“…In 2008, a process involving the use of (1S,2R)-2-aminocyclopentane-1-carboxylic acid ((+)-cispentacin) was developed that was suitable for the preparation of kilogram quantities of a hydroxamate TACE inhibitor (WAY-281418, (1S,2R)-N-hydroxy-2- [4-(2-methylquinolin-4-ylmethoxy)phenylsulfonamido]cyclopentanecarboxamide) [21].…”

Hydrophobic Substituents of the Phenylmethylsulfamide Moiety Can Be Used for the Development of New Selective Carbonic Anhydrase Inhibitors

“…Reagents and starting materials were obtained from commercial sources and used as received. Compound 19 was synthesized according to literature procedure [ 48 ]. The solvents were purified and dried by standard procedures prior to use; petroleum ether (PE) of boiling range 40–60°C was used.…”

“…Compound 20b was obtained from 4-hydroxybenzaldehyde ( 17 ) (1.90 g, 15.58 mmol), PPh 3 (4.27 g, 16.27 mmol), (2-methylquinolin-4-yl)methanol( 19 ) [ 48 ] (2.00 g, 11.54 mmol), and DIAD (3.13 mL, 15.82 mmol). The crude product was purified by column chromatography (PE/EtOAC 3:1 then 1:1) to yield 20b (2.70 g, 85%) as yellow solid.…”

Asymmetric homogeneous hydrogenations at scale

“…In addition, operational simplification could be achieved in the preparation of the catalyst precursor by just adding the HBF 4 ÁOMe 2 to the ruthenium complex and BINAP in methanol and using the mixture as is, rather than preparing the catalyst precursor in a separate operation. 242 Examples where large variations in asymmetric induction can be seen are the reductions of g-substituted b-keto esters using Ru(BINAP) (Ru-10) catalysts. For the alkenes 167a and 167b, high enantioselectivity is observed with the catalyst precursor [NH 2 Et 2 ] + [{RuCl(BINAP)} 2 (m-Cl) 3 ] À with a low hydrogen pressure (50 psig).…”