Development of an NH<sub>4</sub>Cl-Catalyzed Ethoxy Ethyl Deprotection in Flow for the Synthesis of Merestinib

Frederick, Michael O.; Calvin, Joel R.; Cope, Richard F.; LeTourneau, Michael E.; Lorenz, Kurt; Johnson, Martin D.; Maloney, Todd D.; Pu, Yangwei John; Miller, Richard D.; Cziesla, Lauren

doi:10.1021/acs.oprd.5b00240

Cited by 23 publications

(21 citation statements)

References 12 publications

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“…Due to its small footprint, continuous flow technology permits rapid thermal equilibration minimizing heat-up and cool-down times. Based on our previous experience with high temperature, high pressure flow reactions, we sought to apply a PFR to the preparation of 1 . When the use of a PFR is suggested, it is useful to conduct small-scale batch screening reactions to rapidly test discrete variables in parallel.…”

Section: Resultsmentioning

confidence: 99%

Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

Li¹,

Shui-jin²,

Zhu³

et al. 2020

Org. Process Res. Dev.

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We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular S N Ar cyclization. Interestingly, traditional S N Ar conditions resulted in impurity formation. When the starting material 2 was treated with alkali base in polar aprotic solvents, an undesired product regioisomer was observed. The formation of this regioisomer impurity could be suppressed by using a less polar solvent, an organic base, and high temperature. By employing continuous flow technology, these high temperature conditions could be scaled up to produce 540 g of the desired intermediate. The continuous flow reactor allowed for rapid thermal equilibration, which minimized problematic product decomposition by reducing the time that the product was exposed to high temperature.

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Section: Resultsmentioning

confidence: 99%

Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

Li¹,

Shui-jin²,

Zhu³

et al. 2020

Org. Process Res. Dev.

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“…Table 4 h shows the scheme of thermal ethoxyethyl deprotection [25,45]. Three PFR reactors were designed, and all of them were constructed from 7.75 mm i.d.…”

Section: J Flow Chemmentioning

confidence: 99%

“…The lengths of these three reactors were 255, 53, and 153 m, with volumes of 12, 2.5, and 7.2 L, respectively. Accordingly, the reaction conditions were different, as described in Table 4 h [45][46][47]. It is important to note that the second PFR's coil diameter was smaller (< 10 cm) than the other two, and that it fit inside a 10 cm inner-diameter /1.2 m tall steam heating pipe.…”

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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“…A fundamental aspect of this flow-based strategy was the integration of process analytical technology (PAT) such as HPLC or DSC. Online analysis plays a crucial role in automated flow systems and many reports on the resulting benefits can be found in the literature [79][80][81]. For instance, online HPLC analysis allowed for the detection of a disturbance: after several days of processing, the outflow from the SNAr reaction giving 26 began to exhibit elevated levels of pyrazole precursor 25, as well as a deprotected derivative which would be in the form of an HCl salt.…”

Section: Prexasertibmentioning

confidence: 99%

“…The synthetic route is shown in Scheme 7. Previous work from Cziesla et al [79] formed the basis for developing a continuous route that needed to include an effective impurity control strategy. The first step involves a Suzuki-Miyaura cross coupling between indazole bromide 29 and pyrazole 30, followed by the hydrogenation of the pending nitro group of intermediate 31.…”

Section: Merestinibmentioning

confidence: 99%

Continuous Flow Synthesis of Anticancer Drugs

Filippo

Baumann

2021

Molecules

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Continuous flow chemistry is by now an established and valued synthesis technology regularly exploited in academic and industrial laboratories to bring about the improved preparation of a variety of molecular structures. Benefits such as better heat and mass transfer, improved process control and safety, a small equipment footprint, as well as the ability to integrate in-line analysis and purification tools into telescoped sequences are often cited when comparing flow to analogous batch processes. In this short review, the latest developments regarding the exploitation of continuous flow protocols towards the synthesis of anticancer drugs are evaluated. Our efforts focus predominately on the period of 2016–2021 and highlight key case studies where either the final active pharmaceutical ingredient (API) or its building blocks were produced continuously. It is hoped that this manuscript will serve as a useful synopsis showcasing the impact of continuous flow chemistry towards the generation of important anticancer drugs.

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Development of an NH₄Cl-Catalyzed Ethoxy Ethyl Deprotection in Flow for the Synthesis of Merestinib

Cited by 23 publications

References 12 publications

Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Continuous Flow Synthesis of Anticancer Drugs

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Development of an NH4Cl-Catalyzed Ethoxy Ethyl Deprotection in Flow for the Synthesis of Merestinib

Cited by 23 publications

References 12 publications

Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

Continuous Flow Synthesis of Anticancer Drugs

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Development of an NH₄Cl-Catalyzed Ethoxy Ethyl Deprotection in Flow for the Synthesis of Merestinib