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.

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.

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.

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.

Parallel protocol for the selective methylation and alkylation of primary amines.

One of the still unresolved problems in parallel synthesis is the availability of a general and rapid method for the transformation of a primary amine into the corresponding secondary amine without the issue of polyalkylation. Following the Fukuyama method, which is based on the alkylation of o-nitrobenzenesulfonamides, followed by removal of the sulfonyl group, we have developed a simple protocol which can be easily applied to parallel synthesis making use of supported reagents and scavengers. To verify the robustness of the method, a small representative array of secondary amines have been prepared. Moreover, taking advantage of the possibility to use different supported reagents in the same pot, we also prepared, starting from primary amines, a series of differently substituted tertiary amines.