Phosphodiesterase 10A (PDE10A) is one of a superfamily of enzymes that is predominantly expressed in dopaminoreceptive medium spiny neurons of the striatum, and PDE10A inhibitors are expected to be therapeutic agents for neurological disorders. A selective PDE10A inhibitor (1) having the core moiety of a 1,3,5-trisubstituted-pyridazin-4(1H)-one was identified by Takeda Pharmaceutical Company Limited. As a result of process development of compound 1, we have developed an efficient and scalable manufacturing method and manufactured compound 1 on the kilogram scale by this method. This practical preparation of compound 1 involves the following key features: (1) the finding that filling the headspace of the reaction vessel with Ar gas and controlling the flow rate of the gas were important to complete the substitution of an aryl iodide with pyrazole; (2) synthesis of a 3-acetyl-5-methoxy-substituted pyridazin-4(1H)-one via regioselective dimethylaminomethylenation of a diazo compound and simultaneous cyclization; and (3) regioselective ring formation of a 1,5-disubstituted pyrazole through reaction of a dimethylaminomethylene group with phenylhydrazine. In addition, an alternative synthesis via selective alkylation of 1-phenylpyrazole has been discovered.

Practical preparation of a 1,3,5-trisubstituted pyridazin-4(1H)-one using selective C1 unit insertion and cyclization

2019 Fall National Meeting

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