New synthesis of a late-stage tetracyclic key intermediate of lumateperone

Abstract

New approaches have been tested for the synthesis of lumateperone intermediates. As a result of these efforts, a novel synthesis of the late-stage tetracyclic key intermediate of lumateperone starting from the commercially available quinoxaline is described. The tetracyclic skeleton was constructed by the reaction of 1-trifluoroacetyl-4-aminoquinoxaline with ethyl 4-oxopiperidine-1-carboxylate in a Fischer indole synthesis. The inexpensive starting material, the efficient synthetic steps, and the avoidance of the borane-based reduction step provide a reasonable potential for scalability.

Points of Interest in the Chemistry of the Levomepromazine Drug Substance: Recycling of Undesired Enantiomer, Identification of New Phenothiazine Dimers, Synthesis of a Pharmacopeial Impurity, and an Unexpected Rearrangement

“…In continuation of our efforts aiming at the technological − and analytical , development of drug substance manufacturing processes, we also tried to achieve economical improvements in the synthetic procedure leading to levomepromazine [( R )- 1 ]. In order to obtain recovered 2-methoxyphenothiazine ( 2 ) in a reasonable yield and required purity, we aimed to transform the one-pot procedure (see above, Scheme ) into an easily scalable process by isolating and purifying certain intermediates.…”