80928-23-0Relevant articles and documents
Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment
Bianchi, Barbara,Cai, Chunlong,Grand-Guillaume Perrenoud, Alexandre,Hardegger, Leo A.,Humair, Roger,Kaehny, Richard,Lanz, Stephan,Li, Cheng,Li, Jialiang,Mallet, Franck,Rampf, Florian,Shi, Lei,Spoendlin, Christoph,Staüble, Jeannine,Teng, Shangjun,Tian, Xiangguang,Wietfeld, Bernhard,Yang, Yao,Yu, Bo,Zepperitz, Christine,Zhang, Xuesong,Zhang, Yong
, p. 1743 - 1755 (2020/10/27)
We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet-Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet-Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.
An Environmentally Sustainable Mechanochemical Route to Hydroxamic Acid Derivatives
Mocci, Rita,De Luca, Lidia,Delogu, Francesco,Porcheddu, Andrea
supporting information, p. 3135 - 3144 (2016/10/09)
An operationally simple, and cost efficient conversion of carboxylic acids into hydroxamic acid derivatives via a high-energy mechanochemical activation is presented. This ball milling methodology was applied to a wide variety of carboxylic acids dramatically improving purification issues associated with this class of molecules, which still remain one of the main bottlenecks of classical methodologies. (Figure presented.).
N-methylimidazole-catalyzed synthesis of carbamates from hydroxamic acids via the lossen rearrangement
Yoganathan, Sabesan,Miller, Scott J.
supporting information, p. 602 - 605 (2013/04/11)
An efficient, one-pot, N-methylimidazole (NMI) accelerated synthesis of aromatic and aliphatic carbamates via the Lossen rearrangement is reported. NMI is a catalyst for the conversion of isocyanate intermediates to the carbamates. Moreover, the utility of arylsulfonyl chloride in combination with NMI minimizes the formation of often-observed hydroxamate-isocyanate dimers during the sequence. Under the present conditions, lowering of temperatures is also possible, enabling a mild protocol.
