Construction of a chiral central nervous system (CNS)-active aminotetralin drug compound based on a synthesis strategy using multitasking properties of (S)-1-phenylethylamine.
This Account describes the design and development of a scalable synthesis for the drug molecule AR-A2 (1) starting from the discovery route originating in medicinal chemistry. Special emphasis is placed on the introduction of the correct (R) stereochemistry on C2, which was ultimately achieved in a diastereoselective imine-reducing step applying NaBH4. After optimization, this transformation was operated on a large pilot-plant scale (2000 L), offering the desired product (11) in 55% yield and 96% diastereomeric excess at a 100 kg batch size. From a synthesis strategy point of view, the choice of (S)-1-phenylethylamine (9) was crucial not only for its role as a provider of the NH2 functionality and the stereo-directing abilities but also as an excellent protecting group in the subsequent N-arylation reaction, according to the Buchwald-Hartwig protocol. As one of the very first examples in its kind, the latter step was scaled up to pilot manufacturing (125 kg in 2500 L vessel size), delivering an outstanding isolated yield of 95%. This consecutive series of chemical transformations was completed with an environmentally friendly removal of the phenethyl appendage. In addition, an elegant method to synthesize the tetralone substrate 6, as well as a novel and robust procedure to use imidazole as a buffer for the selective formation of the mono-HBr salt of AR-A2, will be briefly described.
Global Process R&D, and Process Chemistry, Process R&D Södertälje, AstraZeneca, 151 85 Södertälje, Sweden. hans-jurgen.federsel@astrazeneca.com
Hans-Jürgen
HJ
Federsel
Martin
M
Hedberg
Fredrik R
FR
Qvarnström
Magnus P T
MP
Sjögren
Wei
W
Tian
D002490:Central Nervous System / Q000187:drug effects*; D015195:Drug Design; D008024:Ligands; D010627:Phenethylamines / Q000737:chemistry* / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D008024:Ligands; D010627:Phenethylamines; D058829:Serotonin 5-HT1 Receptor Antagonists; D013764:Tetrahydronaphthalenes; C095210:tetralin; C033198:1-phenethylamine