Process for the manufacture of inhibitors of kras

Abstract

This invention relates to an efficient and enantioselective synthesis of the spiro-compounds of formula (1) as common intermediate, featuring an asymmetric introduction of the all-carbon quaternary centre in high selectivity and a very efficient one-pot procedure for the C2 elongation to generate the spiro-structure. For the all-carbon quaternary centre, a Tsuji-Trost asymmetric allylic alkylation (AAA) process was designed to develop a sustainable procedure with very low catalyst loading, thereby also facilitating the Pd content control in the product, under practically solvent free conditions. Furthermore, multiple synthetic transformations in a one-pot procedure were implemented by using a one-pot procedure either in form of a three-transformation sequence comprising Hydroboration-Alkylation-Dieckmann Condensation to compound of formula (1) or in form of a five-transformation sequence comprising Hydroboration-Alkylation-Dieckmann Condensation-Hydrolysis-Decarboxylation to compound of formula (9).

Dependencies are inferred from the claim text.