Optimisation of a key cross-coupling reaction towards the synthesis of a promising antileishmanial compound

Raul F Velasco,César Guerrero,Gloria Fra,Alejandra Moure,Juan Miguel-Siles,Maria Teresa Quesada-Campos,Jose Ramon Ruiz-Gomez,Ian H Gilbert,Michael G Thomas,Timothy J Miles

doi:10.1016/j.tetlet.2019.03.068

Raul F Velasco, César Guerrero + Show 8 more

Open Access

https://doi.org/10.1016/j.tetlet.2019.03.068

Copy DOI

Abstract

During the course of a research program aimed at identifying novel antileishmanial compounds, a multi-gram synthesis of N-(trans-4-((4-methoxy-3-((R)-3-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)-2-methylpropane-1-sulfonamide ((R)-1) was required. This letter describes optimisation of the reaction conditions and protecting group strategy for a key Buchwald-Hartwig coupling, delivering the required quantities of (R)-1, as well as further compounds in the series.

Highlights

During the course of a research program aimed at identifying novel antileishmanial compounds, a multigram synthesis of N-(trans-4-((4-methoxy-3-((R)-3-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-6yl)amino)cyclohexyl)-2-methylpropane-1-sulfonamide ((R)-1) was required
During the course of a research program aimed at identifying novel antileishmanial compounds, we discovered a series of N1(1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclohexyl-1,4-trans-diamine compounds that led to GSK3186899/DDD853651 being selected as a pre-clinical development candidate for the treatment of visceral leishmaniasis (Scheme 1) [1,2]
Within the medicinal chemistry program, analogues with less sterically hindered morpholines, such as 10a and 11a (Scheme 3), were synthesised via standard Buchwald-Hartwig coupling conditions in reasonable yields (48–75%) [2,4]. When these conditions were applied to the more sterically hindered 3-methylmorpholine of interest, only around 20% of product was visible by liquid chromatography–mass spectrometry (LCMS) in the reaction mixture after heating at reflux overnight, and pure compound could not be isolated from the crude reaction mixture

Summary

Introduction

During the course of a research program aimed at identifying novel antileishmanial compounds, we discovered a series of N1(1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclohexyl-1,4-trans-diamine compounds that led to GSK3186899/DDD853651 being selected as a pre-clinical development candidate for the treatment of visceral leishmaniasis (Scheme 1) [1,2]. This letter describes optimisation of the reaction conditions and protecting group strategy for a key Buchwald-Hartwig coupling, delivering the required quantities of (R)-1, as well as further compounds in the series. Within the medicinal chemistry program, analogues with less sterically hindered morpholines, such as 10a and 11a (Scheme 3), were synthesised via standard Buchwald-Hartwig coupling conditions in reasonable yields (48–75%) [2,4].

Results

Conclusion