Continuous Flow Synthesis of Thieno[2,3-<i>c</i>]isoquinolin-5(4<i>H</i>)-one Scaffold: A Valuable Source of PARP-1 Inhibitors

Filipponi, P; Ostacolo, Carmine; Novellino, Ettore; Pellicciari, Roberto; Gioiello, Antimo

doi:10.1021/op500074h

Cited by 48 publications

(33 citation statements)

References 38 publications

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“…An efficient multistep method for the continuous‐flow synthesis of thieno[2,3‐ c ]isoquinolin‐5(4 H )‐one‐A (TIQA, 217 ), an important building block for PARP‐1 inhibitors, has been developed by Filipponi and co‐workers . After a Suzuki coupling reaction to generate 3‐phenylthiophene‐2‐carboxylic acid 215 , this is transformed into the corresponding acyl azide and readily cyclized by a thermal Curtius rearrangement.…”

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

“…An efficient multistep methodf or the continuous-flow synthesis of thieno[2,3-c]isoquinolin-5(4H)-one-A (TIQA, 217), an important building block for PARP-1 inhibitors, has been developed by Filipponi and co-workers. [109] After aS uzukic oupling reactiont og enerate 3-phenylthiophene-2-carboxylic acid 215, this is transformed into the corresponding acyl azide and readily cyclized by at hermalC urtius rearrangement.T he authors also employedastatistical design of experimentst os upport the decision and enablet he development of ar obusta nd reliable protocol for large-scale preparation. The large-scale applicability of this protocol was tested by conducting the reactions on am ultigram scale to produce the desired product in high yield and quality.…”

Section: Continuous-flow Curtius Rearrangementmentioning

confidence: 99%

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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: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

Section: Continuous-flow Curtius Rearrangementmentioning

confidence: 99%

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

2018

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“…In our group, we demonstrated how DoE principles enabled the telescopic flow synthesis of thieno[2,3-c]isoquinolin-5(4H)-one-A (TIQ-A, 54), an important pharmacological tool and building block for the development of PARP-1 inhibitors (Scheme 16) [35]. The batch synthesis for this scaffold suffers from some limitations as the moderate overall yield, the use of hazardous reagents, and a laborious protocol.…”

Section: Central Composite Designmentioning

confidence: 99%

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

Gioiello¹,

Filipponi²,

Mostarda³

et al. 2016

J Flow Chem

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The integration of flow systems with statistical design of experiments is emerging as a valuable strategy to develop new synthetic routes towards relevant building blocks, chemical probes, and drug compounds. Optimization by experimental design incorporates statistical algorithms, mathematical models and equations, predicting tools, feedback control, and validation to generate new optimal conditions. Continuous-flow chemistry is ideally suited for this scope, as the integration of in-line analysis is simple; experimental parameters such as temperature, pressure, and flow rate can be easily controlled and fine-regulated; and automation of reaction screening can be accomplished with software assistance. This review article aims to illustrate how the combination of flow synthesizers and design of experiments can be profitable to speed up the development and optimization of more efficient, safer, and reproducible protocols for modern synthetic methods and manufacturing processes.

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“…This has been used in flow chemistry [110], for example, for the preparation of PARP-1 inhibitors [111].…”

Section: Organic Reactions Of Azidesmentioning

confidence: 99%

Hydrazoic Acid and Azides

Bräse

Mende

Jobelius³

et al. 2015

Ullmann's Encyclopedia of Industrial Chemistry

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Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 Inhibitors

Cited by 48 publications

References 38 publications

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

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

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

Hydrazoic Acid and Azides

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