Practical and Scalable Synthesis of S1P1 Receptor Agonist ACT-209905
journal contributionposted on 20.04.2012, 00:00 authored by Gunther Schmidt, Stefan Reber, Martin H. Bolli, Stefan Abele
A practical and scalable route for the fast delivery of 12 kg of S1P1 agonist (ACT-209905) has been developed. ACT-209905 is composed of an amino pyridine group, an oxadiazole spacer, a 2-ethyl-5-methylphenol moiety and a chiral 1-amino-2-propanol side chain. The convergent synthesis consists of 16 steps with 9 isolated intermediates and is chromatography-free. Key building blocks are accessed from low-cost starting materials, such as acetone, diethyl oxalate, cyanoacetamide, and 2-ethyl-5-methyl aniline. A Negishi coupling that was troubled by the use of metal reagents and concomitant metal waste streams has been replaced by a less expensive Guareschi–Thorpe reaction to build up an amino isonicotinic acid. The chiral 1-amino-2-propanol moiety was secured by selective ring-opening of an epoxide with lithium hexamethyldisilazide as an ammonia surrogate, thus omitting the notorious double alkylated byproduct.
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Key building blocksammoniametal waste streams12 kgmaterialNegishiacetoneGuareschilithium hexamethyldisilazidediethyl oxalateAgonistchiralpyridine group16 stepsmoietymetal reagentsisonicotinic acidintermediateS 1P agonistReceptoranilineepoxidealkylated byproductScalable SynthesiscyanoacetamidePracticaloxadiazole spacerscalable routeconvergent synthesis