Michael Gerhard Hoffmann

A new and efficient synthesis of 2-trifluoromethyl substituted pyrroles and ethyl-2,3-bis(ethoxycarbonyl)-1H-pyrrole-1-propionate

Abstract Dirhodium tetraacetate catalyzed decomposition of trifluoromethyl acetyl diazoacetates 6a and 6b in ethyl vinyl ether gives rise to the dihydrofuroates 7a and 7b , respectively, which can be converted into the corresponding 2-(trifluoromethyl)pyrroles. This two step pyrrole synthesis is also suitable for the preparation of ethyl 2,3-bis(ethoxycarbonyl)-1H-pyrrole-1-propinate, an important intermediate for the synthesis of necin bases.

Social housing of non-rodents during cardiovascular recordings in safety pharmacology and toxicology studies.

Introduction The Safety Pharmacology Society (SPS) and National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) conducted a survey and workshop in 2015 to define current industry practices relating to housing of non-rodents during telemetry recordings in safety pharmacology and toxicology studies. The aim was to share experiences, canvas opinion on the study procedures/designs that could be used and explore the barriers to social housing. Methods Thirty-nine sites, either running studies (Sponsors or Contract Research Organisations, CROs) and/or outsourcing work responded to the survey (51% from Europe; 41% from USA). Results During safety pharmacology studies, 84, 67 and 100% of respondents socially house dogs, minipigs and non-human primates (NHPs) respectively on non-recording days. However, on recording days 20, 20 and 33% of respondents socially house the animals, respectively. The main barriers for social housing were limitations in the recording equipment used, study design and animal temperament/activity. During toxicology studies, 94, 100 and 100% of respondents socially house dogs, minipigs and NHPs respectively on non-recording days. However, on recording days 31, 25 and 50% of respondents socially house the animals, respectively. The main barriers for social housing were risk of damage to and limitations in the recording equipment used, food consumption recording and temperament/activity of the animals. Conclusions Although the majority of the industry does not yet socially house animals during telemetry recordings in safety pharmacology and toxicology studies, there is support to implement this refinement. Continued discussions, sharing of best practice and data from companies already socially housing, combined with technology improvements and investments in infrastructure are required to maintain the forward momentum of this refinement across the industry.

A new route to 1,5-disubstituted 4-arylsulfonylpyrazoles by lithiation of 1-methyl-4-arylsulfonylpyrazoles

Abstract The arylsulfonylvinamidinium salts 1 reacted with hydrazine in refluxing ethanol to give rise to 4-arylsulfonylpyrazoles 2 in reasonable yield. Regioselective lithiation of N-methylpyrazoles 3 with LDA followed by treatment with various electrophiles afforded the corresponding 1,5-disubstituted 4-arylsulfonylpyrazoles 5 in good yield.

Parallel synthesis of 1,2,4-triazole derivatives using microwave and continuous-flow techniques

An efficient and convenient solution-phase synthesis of a 1H-1,2,4-triazole library with potential agrochemical activity is reported employing microwave-assisted organic synthesis (MAOS) and continuous-flow microfluidic synthetic methods starting from commercially available 3,5-dibromo-1H-1,2,4-triazole (1). MAOS was used for the synthesis of 5-amino-3-bromo-1,2,4-triazole analogs 3 and for their 3-aryl derivatives 4 via Suzuki–Miyaura coupling with polymer-supported catalyst. A microfluidic hydrogenation reactor integrated into an automated parallel synthesis platform was built and utilized for the reductive dehalogenation reactions providing 5-aminotriazoles (5).Graphical Abstract