Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

Marsini, Maurice A.; Buono, Frédéric G.; Lorenz, Jon C.; Yang, Bing‐Shiou; Reeves, Jonathan T.; Sidhu, Kanwar; Sarvestani, Max; Tan, Zhulin; Zhang, Yongda; Li, Ning; Lee, Heewon; Brazzillo, Jason; Nummy, Laurence J.; Chung, J. C.; Luvaga, Irungu K.; Narayanan, B. A.; Wei, Xudong; Song, Jinhua J.; Roschangar, Frank; Yee, Nathan K.; Senanayake, Chris H.

doi:10.1039/c6gc03123d

Cited by 37 publications

(27 citation statements)

References 72 publications

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“…More recently,M arsini and co-workers proposed ac oncise and scalables ynthesis of CCR1 antagonist 221 using continuous-flow technology. [110] In particular, they achieved the first example of continuous Curtius rearrangement and semi-continuous acid-isocyanate coupling for the direct synthesis of an amide from two carboxylic acid partners. This safe, robust, and green methodology produced compound 221 in high yield and quality on large scale.…”

Section: Continuous-flow Curtius Rearrangementmentioning

confidence: 99%

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addition, the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.

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Section: Continuous-flow Curtius Rearrangementmentioning

confidence: 99%

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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“…These 3 CCR1 antagonists are structurally similar and have a common aryl acid moiety, (1-(4-fluorophenyl)-1H-pyrazolo [3,4-c]pyridine-4-carboxylic acid (10) coupled via an amide bond to (2-methylsulfonyl-4-pyridyl)methaneamine (11), 1-(2-(methylsulfonyl)pyridin-4-yl) cyclopropan-1-amine (12), 14 and (S)-1-(2-(methylsulfonyl) pyridin-4-yl)propan-1-amine (13), 15 respectively (Figure 1). Our efforts were concentrated on the synthesis of this acid as a common intermediate to access these compounds labeled with carbon-13 and carbon-14.…”

Section: Resultsmentioning

confidence: 99%

Potent and selective CC chemokine receptor 1 antagonists labeled with carbon‐13, carbon‐14, and tritium

Latli

Hrapchak

Cheveliakov

et al. 2018

Labelled Comp Radiopharmac

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“…High-scale continuous flow preparation involving a Curtius rearrangement of (a) a protected amine derivative and (b) a CCR1 antagonist (semicontinuous). [181] of total residence time. Real-time monitoring of the reactor effluent was successfully implemented using a UV detector.…”

Section: Eurjocmentioning

confidence: 99%

Continuous Flow Organophosphorus Chemistry

2020

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Organophosphorus derivatives are widespread compounds that chemists find from the bench to the plant, with numerous daily life applications. Besides their common utility for a wide range of notorious reactions such as the Wittig and Horner‐Wadsworth‐Emmons olefinations, the Arbuzov reaction, the Staudinger reaction, the Mitsunobu reaction as well as ligands for a large variety of organometallic complexes, organophosphorus compounds have also found numerous applications as active pharmaceutical ingredients and agrochemicals. Some organophosphorus derivatives are also infamously known as Chemical Warfare Agents. Within the context of generalized adoption of new process technologies in the Chemistry Toolbox, this review intends to give an update on the most recent and significant advances in continuous flow organophosphorus chemistry. Selected examples in methodology, total synthesis and for the preparation of industrially relevant targets are discussed for illustrating the assets of flow chemistry.

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Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement

Abstract: A convergent and robust synthesis of a developmental CCR1 antagonist is described using continuous flow technology.

Cited by 37 publications

References 72 publications

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

Potent and selective CC chemokine receptor 1 antagonists labeled with carbon‐13, carbon‐14, and tritium

Continuous Flow Organophosphorus Chemistry

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