Development of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor BMS-986260

Abstract

A scalable route to the small molecule TGFβR1 inhibitor BMS-986260 (1) was developed. This alternative approach circumvented the purification of intermediates by column chromatography and provided access to multikilogram quantities of the key intermediate, 6. The safety aspects of the synthetic approach to the other fragment of the API (TosMIC 10) were critically evaluated, and a robust process for its large-scale synthesis was successfully demonstrated.

Transition-metal-free three-component acetalation-pyridylation of alkenes via photoredox catalysis

“…Aldehyde group presents a key synthetic precursor of valuable functional groups, such as alcohols, carboxylic acids, and alkenes, whereby it plays an essential role in organic synthesis and structure modification of drugs [27][28][29][30][31][32][33]. In addition, aldehyde acted as a covalent group is widely used in chemical biology research for "undruggable" targets [34,35].…”

Improved Synthetic Process of Baloxavir Marboxil Intermediate 3-Benzyloxy-4-oxo-4H-pyran-2-carboxylic Acid

“…The primary task of the optimization in this step was the replacement of the solvent DMSO used in the original route and DMF in other similar cases. ,,, Though such dipole solvents may increase reaction speed and conversion, they could produce large aqueous waste streams and lead to high energy inputs when separating products and removing or recovering these solvents for large-scale manufacturing . After the initial screening of solvents with high boiling points (see Table S1 in the Supporting Information), n -BuOAc and toluene showed promise with a total reaction time over 30 h under the catalysis of an amphoteric additive betaine ( N , N , N -trimethylglycine inner salt).…”

“…However, a few remaining challenges necessitated further optimization: the installation of the enamine function group required up to 5 equiv of reagent 14 . This requirement is consistent with other cases where 14 was used to form an enamine with a methyl group upon an aromatic heterocycle. , Furthermore, overcharged reagent 14 could be converted to DMF during workup, leading to significant environmental concerns due to the disposal of enormous nitrogenous wastewater. the oxidation sequence from methyl to carboxylic acid involved the column chromatographic isolation of the aldehyde intermediate 5 , leading to poor volume efficiency. DMSO as a solvent may cause environmental issues upon scale-up. , …”

“…the installation of the enamine function group required up to 5 equiv of reagent 14 . This requirement is consistent with other cases where 14 was used to form an enamine with a methyl group upon an aromatic heterocycle. , Furthermore, overcharged reagent 14 could be converted to DMF during workup, leading to significant environmental concerns due to the disposal of enormous nitrogenous wastewater.…”