合成路线1

Two main strategies have been used to synthesize SQ-109, including a solid-phase approach (1), which was later adapted for solutionphase synthesis (2). In the solid-phase strategy, Rink acid resin is activated at room temperature using triphenylphosphine and hexachloroethane in THF. The activated resin is then loaded with a solution of EtN(i-Pr)2 and (2E)-3,7-dimethylocta-2,6-dien-1-amine (geranylamine, I) in dichloroethane for 8 hours at 45 °C, followed by 6-8 hours at room temperature. The resulting geranylamine-attached resin (II) is then loaded with pyridine and chloroacetyl chloride (III) in THF for 8 hours at 45 °C, followed by 6-8 hours at room temperature to give resin-attached N-geranyl-a-chloroacetamide (IV), which is loaded with EtN(i-Pr)2 and a suspension of 2-adamantamine hydrochloride (V) in DMF at 70-75°C for 16 hours to give resin-attached N-geranyl-N’-(2-adamantyl)glycinamide (VI). Glycinamide (VI) is then reduced in anhydrous THF by adding Red-Al in toluene and stirring for 4 hours at room temperature to yield resin-attached N-geranyl-N’-(2-adamantyl)ethane-1,2-diamine (VII). In the last step, the resin is loaded with TFA and dichloromethane followed by the addition of MeOH to cleave the resin-linked product before filtration. The filtrate is collected and dried to give the trifluoroacetate salt of N-geranyl-N’-(2-adamanthyl)ethane-1,2-diamine (SQ-109), which is further purified by HPLC to give the diacetate salt (3). Scheme 1.