New insights into scale up processing and C-S bond formation reactions

This thesis describes the development of a new microwave-mediated methodology for C–S bond formation and the issues regarding scaling up heterocyclic transformations. Chapter 1 provides an overview on the current understanding of microwave-mediated synthesis and on the use of microwave technology in copper- and palladium-mediated synthesis. A separate part is dedicated to the current advancements in the use of flow reactors within the chemical community. Chapter 2 describes the application of the current batch and continuous flow technology for the scale-up of selected heterocyclic transformations, starting with the well known Bohlmann- Rahtz pyridine synthesis and moving to other reactions, including pyrimidine and Hantzsch dihydropyridine synthesis. Chapter 3 describes the development of a new methodology for the microwave-mediated C–S bond formation, starting from an investigation on the current available methods and moving to the application of new methodology to the synthesis of a library of compounds. Further application was found in the synthesis of a drug candidate with anti-ageing properties and in the synthesis of a new class of anti-HIV compounds.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

New insights into scale up processing and C-S bond formation reactions

This thesis describes the development of a new microwave-mediated methodology for C–S bond formation and the issues regarding scaling up heterocyclic transformations. Chapter 1 provides an overview on the current understanding of microwave-mediated synthesis and on the use of microwave technology in copper- and palladium-mediated synthesis. A separate part is dedicated to the current advancements in the use of flow reactors within the chemical community. Chapter 2 describes the application of the current batch and continuous flow technology for the scale-up of selected heterocyclic transformations, starting with the well known Bohlmann- Rahtz pyridine synthesis and moving to other reactions, including pyrimidine and Hantzsch dihydropyridine synthesis. Chapter 3 describes the development of a new methodology for the microwave-mediated C–S bond formation, starting from an investigation on the current available methods and moving to the application of new methodology to the synthesis of a library of compounds. Further application was found in the synthesis of a drug candidate with anti-ageing properties and in the synthesis of a new class of anti-HIV compounds

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

The Bohlmann–Rahtz pyridine synthesis and the Hantzsch dihydropyridine synthesis can be carried out in a microwave flow reactor or using a conductive heating flow platform for the continuous processing of material. In the Bohlmann–Rahtz reaction, the use of a Brønsted acid catalyst allows Michael addition and cyclodehydration to be carried out in a single step without isolation of intermediates to give the corresponding trisubstituted pyridine as a single regioisomer in good yield. Furthermore, 3-substituted propargyl aldehydes undergo Hantzsch dihydropyridine synthesis in preference to Bohlmann–Rahtz reaction in a very high yielding process that is readily transferred to continuous flow processing

A microwave-assisted synthesis of triphenodioxazines [TPDOs]

A convenient and efficient method for the synthesis of triphenodioxazines [TPDOs] 1 by oxidative cyclisation of 2,5-bis-(arylamino)-3,6-dichlorocyclohexa-2,5-diene-1,4-diones 6 using potassium persulfate as the oxidising agent in 95‑97% sulfuric acid triggered by microwave irradiation is described

Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745

Microwave irradiation promotes the rapid and efficient reaction of a thiophenol and aryl or heteroaryl halide using a copper or palladium catalyst and a range of ligands, depending upon substrate. Of particular utility is the use of copper(I) iodide (5 mol %) and trans-cyclohexane-1,2-diol as ligand under basic conditions and microwave irradiation to give the corresponding sulfide in high yield. This method for C-S bond formation is applied in the four-step synthesis of the clinical candidate VX-745 in 38% overall yield. The inhibitory activity of VX-745 against p38alpha MAPK is confirmed in Werner syndrome dermal fibroblasts at 1.0 microM concentration by immunoblot assay

Gram-scale synthesis of the p38α MAPK-inhibitor VX-745 for preclinical studies into Werner syndrome

Background: The ATP-competitive p38α MAPK inhibitor VX-745 exhibits an exquisite kinase selectivity profile, is effective in blocking p38 stress signaling in Werner syndrome dermal fibroblasts, has efficacy in clinical trials and may have therapeutic value against Werner syndrome. Previous synthetic routes, however, have only resulted in milligram quantities suitable for cell-based studies, whereas gram quantities would be required for in vivo use. Results & discussion: Microwave irradiation using a stop–flow monomodal microwave reactor has been found to facilitate scale-up of the synthesis of VX-745. Ullmann-type C–S bond formation using thiophenol, chloropyridazine, copper(I) catalyst and diol ligand proceeds rapidly and efficiently in this apparatus for elaboration to the pyrimido[1,6-b]pyridazinone core of VX-745 on gram scale and with good overall yield. Conclusion: This method delivers the p38 inhibitor VX-745 in sufficient quantities for preclinical studies to rescue the aging phenotype in Werner syndrome

Continuous flow processing from microreactors to mesoscale: the Bohlmann-Rahtz cyclodehydration reaction

The cyclodehydration of a number of Bohlmann-Rahtz aminodienones exemplifies the use of continuous flow processing to transfer operations from commercial microreactors and microwave batch reactors to mesoscale production using different technology platforms, including a microwave flow reactor