The quest for lead-oriented synthesis proposed by medicinal chemistry from GSK in early 2010s have prompted for design and study of low-molecular-weight, hydrophilic, conformationally restricted and sp3-enriched molecular scaffolds. This trend leads to creation of criteria for the building blocks design in 2015 by AZ co-workers. The 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines bearing orthogonally protected functional groups meet the above mentioned criteria and was highlighted in AZ paper. In spite of plenty papers and patents which described synthetic approaches to the scaffold, convenient, flexible and appropriate for easy scale up approach still needed. As a part of our ongoing efforts on design and synthesis of advanced building blocks for medicinal chemistry, we have turned our attention to tetrahydropyrazolo[1,5-a]pyrazines. The new approach towards multigram preparation of these compounds was developed. The synthesis started from commercial available substituted 1H-pyrazole-5-carboxylic acids 1. The assembling of unsaturated pyrazine ring with subsequent catalytic hydrogenation leads to desired building blocks having one functional amino group 6. The following iodation of the Boc-derivatives with NIS led to iodinated derivatives 7, which rapidly transmetalated with iPrMgCl give corresponding Grignard reagent 8 able to transformation into wide range of additional functional groups such COOH, CHO, SO2Na, BPin and SO2Cl. A little bit lately direct carbonilation of the corresponding iodides 7 with CO in presents of PdCl2Dppf into carbonyl derivative 10 have been performed with better yield. Taking into account the new trend of sulfenilimines using in MedChem the corresponding thiol 15 was converted to compound 18 having imino-group able to further functionalization. Also were found conditions of chiral HPLC separation of racemic compound 18 to both enantiomers.

4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrazine: Lead-oriented scaffold with three diversity points

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.