Process development work to provide an efficient manufacturing route to a MCHr1 antagonist is presented herewith. Features of this development work include a scalable manufacturing route to the useful 6-oxa-2-azaspiro[3.3]­heptane building block and the use of a (soluble) alternative to sodium triacetoxyborohydride.

A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler− Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal−Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4-chlorophenylsulfenyl chloride. In this manner, the 1,2,3,4-substitution pattern of the AZD1981 core was regiospecifically established in a concise and efficient telescoped sequence. Accordingly, AZD1981 was obtained in 40% overall yield in six chemical steps, with two isolated crystalline intermediates.

The synthesis of the title salt, C20H23N2O2 +·Cl−, was carried out with a precursor of known absolute configuration (R) and the X-ray analysis confirmed that the product retained the absolute configuration. In the crystal, the dominant packing motif is a chain running along [010] generated by N—H⋯Cl hydrogen bonding. C—H⋯O and C—H⋯Cl inter­actions are also observed.