An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

• Nicky J. Willis,
• Elliott D. Bayle,
• George Papageorgiou,
• David Steadman,
• Benjamin N. Atkinson,
• William Mahy and
• Paul V. Fish

Beilstein J. Org. Chem. 2019, 15, 2790–2797, doi:10.3762/bjoc.15.271

• 1 (or 17) which combines Notum inhibition with CNS penetration would be a valuable chemical probe for investigating the role of Notum in disease models. Keywords: brain penetration; 1-chloro-1,2-benziodoxol-3-one; electrophilic chlorination; LP-922056; Notum inhibitor; Introduction The Wnt

• others in evaluating these results with the objective of solving this challenge (see Supporting Information File 1, Table S4 and Supporting Information File 2). Our own efforts took us to an alternative chemotype [21]. Conclusion An improved, scalable synthesis of Notum inhibitor 1 is reported. Key

• challenge. Chemical structure of Notum inhibitor LP-922056 (1). Concentrations of 1 in mouse following oral administration (p.o.) at 10 mg/kg. Synthesis of LP-922056 (1). Reagents and conditionsa: (a) (COCl)2 (3.3 equiv), DMF, CH2Cl2, 55 °C , 16 h, 63–78%; (b) NaOMe (5 equiv), 1,4-dioxane, 0 °C then rt, 16