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Synthesis of a Highly Functionalized Quinazoline Organozinc toward KRAS G12C Inhibitor Divarasib (GDC-6036), Enabled through Continuous Flow Chemistry
25 Jun 2024 | Contributor(s):: Kelly, Sean M., Lebl, René, Malig, Thomas C., Bass, Thomas M., Kummli, Dominique, Kaldre, Dainis, Orcel, Ugo, Tröndlin, Lars, Linder, David, Sedelmeier, Joerg, Bachmann, Stephan, Han, Chong, Zhang, Haiming, Gosselin, Francis
The development of a scalable continuous flow process to synthesize a densely functionalized quinazoline organozinc intermediate toward KRAS G12C inhibitor divarasib (GDC-6036) is reported herein. A traditional cryogenic batch metalation process was initially employed, but instability of the...
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Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib
25 Jun 2024 | Contributor(s):: Kaldre, Dainis, Stocker, Severin, Linder, David, Reymond, Helena, Schuster, Andreas, Lamerz, Jens, Hildbrand, Stefan, Püntener, Kurt, Berry, Malcolm, Sedelmeier, Jörg
This article outlines the development of a continuous flow process for the manufacture of a key intermediate of the active pharmaceutical ingredient ipatasertib for the treatment of metastatic castration-resistant prostate cancer and triple-negative metastatic breast cancer. The reaction sequence...
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A Flow Process Built upon a Batch Foundation—Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis
25 Jun 2024 | Contributor(s):: Lim, John Jin, Arrington, Kenneth, Dunn, Anna L., Leitch, David C., Andrews, Ian, Curtis, Neil R., Hughes, Mark J., Tray, Daniel R., Wade, Charles E., Whiting, Matthew P., Goss, Charles, Liu, Yangmu Chloe, Roesch, Brian M.
This paper describes recent efforts to apply flow technology in the preparation of the key amino alcohol intermediate 3b so as to address manufacturability issues present in the batch process of a PRMT5 inhibitor. The continuous process, one of the first reported pharmaceutical processes to use...
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Continuous Selective Hydrogenation of Refametinib Iodo-nitroaniline Key Intermediate DIM-NA over Raney Cobalt Catalyst at kg/day Scale with Online UV–Visible Conversion Control
25 Jun 2024 | Contributor(s):: Said, Mourad Ben, Baramov, Todor, Herrmann, Tanja, Gottfried, Michael, Hassfeld, Jorma, Roggan, Stefan
The continuous selective hydrogenation of the iodo-nitroaromatic refametinib active pharmaceutical ingredient (API) intermediate (2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (DIM-NA) to the corresponding iodo-aniline...
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Development of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed Hydrogenolysis
25 Jun 2024 | Contributor(s):: Zaborenko, Nikolay, Linder, Ryan J., Braden, Timothy M., Campbell, Bradley M., Hansen, Marvin M., Johnson, Martin D.
The design, development, and implementation of a pilot-scale continuous hydrogenolysis in a catalytic packed bed to generate a starting material is described. Control of a critical defluorination impurity under the reaction conditions has been achieved by reducing residence time inside the...
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Sarah George
https://cmkc.usp.org/members/1118
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The Effect of Ultrasound on the Crystallisation of Paracetamol in the Presence of Structurally Similar Impurities
09 Jun 2023 | Contributor(s):: Nguyen, TTH, Khan, ABruce, LM, Forbes, C, O'Leary, RL, Price, CJ
Sono-crystallisation has been used to enhance crystalline product quality particularly in terms of purity, particle size and size distribution. In this work, the effect of impurities and ultrasound on crystallisation processes (nucleation temperature, yield) and crystal properties (crystal size...