Process for the preparation of dispiro 1,2,4-trioxolane antimalarials (OZ277)

A process for the preparation of a compound of Formula I, salt of the free base cis-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl)amino]carbonyl]methyl]-1′,2′,4′-trioxaspiro [4.5] decane

• wherein X is an anion selected from acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, glycolate, malonate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluene sulfonate or undecanoate, the process comprising,
• a) reacting a compound of Formula II (wherein R is alkyl) with a compound of Formula III (wherein R is alkyl)
• to give a compound of Formula IV;
• b) hydrolyzing the compound of Formula IV to give a compound of Formula V;
• c) reacting the compound of Formula V with an activating agent that forms a mixed anhydride with the compound of Formula V and 1,2-diamino-2-methyl propane to give a compound of Formula VI;
• and
• d) reacting the compound of Formula VI with an acid of Formula HX (wherein X is the same as defined earlier) to give a compound of Formula I.