551909-81-0Relevant 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)
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.
Blue Light-Promoted N?H Insertion of Carbazoles, Pyrazoles and 1,2,3-Triazoles into Aryldiazoacetates
Stivanin, Mateus L.,Fernandes, Alessandra A. G.,da Silva, Amanda F.,Okada, Celso Y.,Jurberg, Igor D.
supporting information, p. 1106 - 1111 (2020/01/25)
Blue light irradiation of aryldiazoacetates leads to the formation of free carbenes, which can react with carbazoles, pyrazoles and 1,2,3-triazoles to afford the corresponding N?H inserted products. These reactions are performed under air and at room temperature, allowing the mild preparation of a variety of motifs found in biologically relevant targets. (Figure presented.).
HETEROCYCLIC COMPOUNDS AND METHODS OF THEIR USE
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Page/Page column 46; 47, (2015/02/02)
The present invention relates generally to compounds that are useful in antagonizing the angiotensin II type 2 (AT2) receptor. More particularly, the invention relates to substituted isoquinoline compounds and their use as AT2 receptor antagonists. Pharmaceutical compositions comprising the compounds and their use in modulating the AT2 receptor and therapies that require modulation of the AT2 receptor are described.
SALT AND SOLVATES OF A TETRAHYDROISOQUINOLINE DERIVATIVE
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Page/Page column 24, (2012/02/03)
(S)-2-(Diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline carboxylic acid in substantially pure form is described together with its sodium salt and solvates. Methods for preparing the compound, its sodium salt and its solvates a
