title: Practical synthesis, separation, and stereochemical assignment of the PMPA pro-drug GS-7340.
abstract: The practical synthesis of a mixed phenoxy-amidate derivative of PMPA with high oral bioavailability and favorable pharmacokinetics is described. The non-stereoselective synthetic route produces a 1:1 mixture of two diastereomers at phosphorous. Simulated moving bed chromatography using Chiralpak AS enabled kilo-scale isolation of the more potent diastereomer (GS-7340). The GS-7340 phosphorous chiral center was found to be (S) by X-ray crystallography.
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chapman
authors.forename: M
authors.initials: M
authors.lastname: Kernan
authors.forename: E
authors.initials: E
authors.lastname: Prisbe
authors.forename: J
authors.initials: J
authors.lastname: Rohloff
authors.forename: M
authors.initials: M
authors.lastname: Sparacino
authors.forename: T
authors.initials: T
authors.lastname: Terhorst
authors.forename: R
authors.initials: R
authors.lastname: Yu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000493:pharmacokinetics; D000409:Alanine; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification; D013237:Stereoisomerism; D000068698:Tenofovir / Q000031:analogs & derivatives
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine