A Practical and Robust Multistep Continuous Process for Manufacturing 5-Bromo-<i>N</i>-(<i>tert</i>-butyl)pyridine-3-sulfonamide

Yu, Miao; Strotman, Neil A.; Savage, Scott A.; Leung, Simon; Ramı́rez, Antonio

doi:10.1021/acs.oprd.9b00254

Cited by 13 publications

(10 citation statements)

References 31 publications

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“…The highly exothermic nature of the Li–Br exchange dictates the slow combination of n -BuLi and 6 to control the reaction temperature . The adiabatic temperature rise could be as high as 61.9 °C under a worst-case scenario .…”

Section: Results and Discussionmentioning

confidence: 99%

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Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor—Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors

Barnhart

Dion

et al. 2021

Org. Process Res. Dev.

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Process development for the synthesis of a second generation β-amyloid-cleaving enzyme (BACE1) inhibitor (1) is described. The lithiothiazole addition to the isoxazolene (5) under batch conditions was not scalable because of reaction gelling and anion instability. A continuous stirred-tank reactor flow process was developed and successfully executed on the 70 kg scale in multiple runs. In a head-to-head comparison between the continuous and batch processes, the former was clearly superior as it gave a higher yield (80 vs 63%) of the adduct (4) and better reaction control for handling the unstable lithiothiazole as a reaction intermediate. Subsequently, 4 underwent Pd-catalyzed amination with t-butyl carbamate, reductive cleavage of the N–O bond, thioamidine cyclization, and deprotection of the Boc group to provide hydropyranothiazine 2. The synthesis of 1 was completed by amidation with 5-(difluoromethoxy)picolinic acid and the successive deprotection of the benzamide group with either Silicycle-diamine or l-lysine.

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Section: Results and Discussionmentioning

confidence: 99%

“…Both plug-flow reactor (PFR) and continuous stirred-tank reactor (CSTR) approaches were considered. A PFR approach was first tested . The solution of 6 in toluene at RT was pumped into a coil and mixed with n -BuLi solution in hexane/toluene via a T-mixer.…”

Section: Results and Discussionmentioning

confidence: 99%

Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor—Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors

Barnhart

Dion

et al. 2021

Org. Process Res. Dev.

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“…There are other publications that report on reactions performed in PFRs [23,[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63], which are not discussed in detail here.…”

Section: J Flow Chemmentioning

confidence: 99%

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

2021

J Flow Chem

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Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large part motivated by the many advantages of continuous manufacturing (e.g., low cost, quality assurance, shortened lead time). As chemical reactions are fundamental to any drug production process, the selection of reactor and its design are critical to enhanced performance such as improved selectivity and yield. In this article, relevant theories, and models, as well as their required input data are summarized to assist the reader in these tasks, focusing on continuous reactions. Selected examples that describe the application of plug flow reactors (PFRs) and continuous-stirred tank reactors (CSTRs)-in-series within the pharmaceutical industry are provided. Process analytical technologies (PATs), which are important tools that provide real-time in-line continuous monitoring of reactions, are recommended to be considered during the reactor design process (e.g., port design for the PAT probe). Finally, other important points, such as density change caused by thermal expansion or solid precipitation, clogging/fouling, and scaling-up, are discussed.

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“…However, the industrial batch-scale presented some failures such as limited conversion, low yield, and problems with the instability of the heteroaryl Grignard reagent. Therefore, in the same year, BMS's researchers [91] adopted a new continuous strategy with well-controlled cooling and a sequence of static mixers in the set-up to synthesize the key intermediate on a multikilogram scale (Fig. 50).…”

Section: Api Manufacturing Under Continuous Flow Conditionsmentioning

confidence: 99%

Improved Synthesis of Bioactive Molecules Through Flow Chemistry

Souza

Paez

Assis³

et al. 2021

Topics in Medicinal Chemistry

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This chapter presents the major impacts of continuous flow technologies on the development of syntheses of bioactive natural product molecules and active pharmaceutical ingredients (APIs). We emphasize scalable and robust protocols covering the literature from 2015 to mid-2020. In the case of continuous manufacturing of APIs we decided to cover examples with relevance considering the advanced stage for industrial production, the molecular complexity, and the importance of each API for Big Pharma.

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A Practical and Robust Multistep Continuous Process for Manufacturing 5-Bromo-N-(tert-butyl)pyridine-3-sulfonamide

Cited by 13 publications

References 31 publications

Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor—Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors

Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor—Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Improved Synthesis of Bioactive Molecules Through Flow Chemistry

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