173338-07-3Relevant articles and documents
Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5-C6 Disconnection and CO2H-NH2 Equivalence
Cini, Elena,Banfi, Luca,Barreca, Giuseppe,Carcone, Luca,Malpezzi, Luciana,Manetti, Fabrizio,Marras, Giovanni,Rasparini, Marcello,Riva, Renata,Roseblade, Stephen,Russo, Adele,Taddei, Maurizio,Vitale, Romina,Zanotti-Gerosa, Antonio
, p. 270 - 283 (2016/03/04)
A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the C5 carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale.
A stereoselective catalytic nitroaldol reaction as the key step in a strategy for the synthesis of the renin inhibitor aliskiren
Rossi, Sergio,Benaglia, Maurizio,Porta, Riccardo,Cotarca, Livius,Maragni, Paolo,Verzini, Massimo
, p. 2531 - 2537 (2015/04/22)
Aliskiren is the first-in-class orally active direct renin inhibitor. It was approved in 2007 for the treatment of hypertension. We have designed a new strategy for the convergent synthesis of aliskiren that involves a catalytic stereoselective nitroaldol reaction as the key step. A new enantiopure nitroalkane (synthon A1), prepared in only three steps from a commercially available enantiopure 2-(arylmethyl)-3-methyl butanol derivative, was successfully used in a copper-catalysed Henry reaction to give a nitrolactone intermediate in which the correct configuration for the final product was established at all four stereocentres. Nitro-group reduction, Boc-protection of the resulting amine, aminolysis of the lactone with 3-amino-2,2-dimethylpropionamide, and finally Boc-deprotection led to the enantiopure renin inhibitor aliskiren.
Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical
Heider, Patrick L.,Born, Stephen C.,Basak, Soubir,Benyahia, Brahim,Lakerveld, Richard,Zhang, Haitao,Hogan, Rachael,Buchbinder, Louis,Wolfe, Aaron,Mascia, Salvatore,Evans, James M. B.,Jamison, Timothy F.,Jensen, Klavs F.
, p. 402 - 409 (2014/04/17)
The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h-1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid-liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90-95%) under closed-loop control despite process disturbances.
