title: Synthesis and determination of absolute configuration of a non-peptidic αvβ6 integrin antagonist for the treatment of idiopathic pulmonary fibrosis.
abstract: A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).
authors.affiliation: Medicinal Chemistry, Fibrosis and Lung Injury DPU, Respiratory Therapeutic Area, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK. pan.a.procopiou@gsk.com.
authors.forename: Niall A
authors.initials: NA
authors.lastname: Anderson
authors.forename: Ian B
authors.initials: IB
authors.lastname: Campbell
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Fallon
authors.forename: Sean M
authors.initials: SM
authors.lastname: Lynn
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
authors.forename: John M
authors.initials: JM
authors.lastname: Pritchard
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: Steven L
authors.initials: SL
authors.lastname: Sollis
authors.forename: Lee R
authors.initials: LR
authors.lastname: Thorp
mesh_terms: D000951:Antigens, Neoplasm; D020148:Butyric Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D060326:Chemistry Techniques, Synthetic; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy*; D016023:Integrins / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013237:Stereoisomerism
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D011759:Pyrrolidines; C073878:integrin alphavbeta6; D020148:Butyric Acid